Low hygroscopic aripiprazole drug substance and processes for the preparation thereof

ABSTRACT

The present invention provides low hygroscopic forms of aripiprazole and processes for the preparation thereof which will not convert to a hydrate or lose their original solubility even when a medicinal preparation containing the anhydrous aripiprazole crystals is stored for an extended period.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 11/790,604,filed Apr. 26, 2007, now pending, which is a division of applicationSer. No. 10/333,244, now abandoned, which is a  371 of InternationalApplication No. PCT/JP02/09858, filed Sep. 25, 2002, which claimspriority of Japanese Application Nos. JP 2001-290645, filed Sep. 25,2001, and JP 2001-348276, filed Nov. 14, 2001, and of CanadianApplication No. CA 2379005, filed Mar. 27, 2002, the contents of all ofwhich are incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention

The present invention relates to an improved form of aripiprazole havingreduced hygroscopicity and processes for the preparation of thisimproved form.

Background of the Invention

Aripiprazole,7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril or7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2(1H)-quinolinone,is an atypical antipsychotic agent useful for the treatment ofschizophrenia (U.S. Pat. Nos. 4,734,416 and 5,006,528). Schizophrenia isa common type of psychosis characterized by delusions, hallucinationsand extensive withdrawal from others. Onset of schizophrenia typicallyoccurs between the age of 16 and 25 and affects 1 in 100 individualsworldwide. It is more prevalent than Alzheimer's disease, multiplesclerosis, insulin-dependent diabetes and muscular dystrophy. Earlydiagnosis and treatment can lead to significantly improved recovery andoutcome. Moreover, early therapeutic intervention can avert costlyhospitalization.

According to Example 1 of Japanese Unexamined Patent Publication No.191256/1990, anhydrous aripiprazole crystals are manufactured forexample by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with1-(2,3-dichlorophenylpiperadine and recrystallizing the resulting rawanhydrous aripiprazole with ethanol. Also, according to the Proceedingsof the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8,1996), anhydrous aripiprazole crystals are manufactured by heatingaripiprazole hydrate at 80° C. However, the anhydrous aripiprazolecrystals obtained by the aforementioned methods have the disadvantage ofbeing significantly hygroscopic.

The hygroscopicity of these crystals makes them difficult to handlesince costly and burdensome measures must be taken in order ensure theyare not exposed to moisture during process and formulation. Exposed tomoisture, the anhydrous form can take on water and convert to a hydrousform. This presents several disadvantages. First, the hydrous forms ofaripiprazole have the disadvantage of being less bioavailable and lessdissoluble than the anhydrous forms of aripiprazole. Second, thevariation in the amount of hydrous versus anhydrous aripiprazole drugsubstance from batch to batch could fail to meet specifications set bydrug regulatory agencies. Third, the milling may cause the drugsubstance, Conventional Anhydrous Aripiprazole, to adhere tomanufacturing equipment which may further result in processing delay,increased operator involvement, increased cost, increased maintenanceand lower production yield. Fourth, in addition to problems caused byintroduction of moisture during the processing of these hygroscopiccrystals, the potential for absorbance of moisture during storage andhandling would adversely affect the dissolubility of aripiprazole drugsubstance. Thus shelf-life of the product could be significantlydecreased and/or packaging costs could be significantly increased. Itwould be highly desirable to discover a form of aripiprazole thatpossessed low hygroscopicity thereby facilitating pharmaceuticalprocessing and formulation operations required for producing dosageunits of an aripiprazole medicinal product having improved shelf-life,suitable dissolubility and suitable bioavailability.

Also, Proceedings of the 4th Japanese-Korean Symposium on SeparationTechnology (Oct. 6-8, 1996) state that, anhydrous aripiprazole crystalsexist as type-I crystals and type-II crystals; the type-I crystals ofanhydrous aripiprazole can be prepared by recrystallizing from anethanol solution of aripiprazole, or by heating aripiprazole hydrate at80° C.; and the type-II crystals of anhydrous aripiprazole can beprepared by heating the type-I crystals of anhydrous aripiprazole at 130to 140° C. for 15 hours.

By the aforementioned methods, anhydrous aripiprazole type-II crystalshaving high purity can not be easily prepared in an industrial scalewith good repeatability.

SUMMARY OF THE INVENTION

Thus according to the present invention is provided a form ofaripiprazole having reduced hygroscopicity and which is more amenable topharmaceutical processing and formulation. The inventors of the presentinvention have discovered that this reduced-hygroscopic form ofAripiprazole is a crystalline substance defined herein as AnhydrousAripiprazole Crystals B. A particular process for the preparation ofthis anhydrous crystalline substance has also been discovered andcomprises yet another aspect of the present invention. Particularly, itwas discovered as part of the present invention that in order to produceAnhydrous Aripiprazole Crystals B having the desired pharmaceuticalproperties and utilizing the most efficient process, Hydrate A, asdefined herein, would have to serve as the intermediate. It was alsodiscovered that a particular sequence of processing had to beimplemented in order to form Hydrate A. It was discovered that thepreparation of Hydrate A required milling what is defined herein asConventional Hydrate. Then, Hydrate A can be transformed into AnhydrousAripiprazole Crystals B through suitable heating as defined herein.Surprisingly, if the Conventional Hydrate is first heated and thenmilled, serious agglomeration sets in rendering the processingcommercially unsuitable.

An object of the present invention is to provide novel anhydrousaripiprazole crystals.

Moreover, another object of the present invention is to provideanhydrous aripiprazole crystals which neither easily convert intohydrates nor substantially decrease the original solubility, even when apharmaceutical composition comprising anhydrous aripiprazole is storedfor a long period of time.

Further object of the present invention is to provide preparationmethods, in order to obtain anhydrous aripiprazole crystals having highpurity in an industrial scale with good repeatability.

The present inventors have conducted research works aimed to attain theaforementioned objects. In the course of the research, they have foundthat the desired anhydrous aripiprazole crystals can be obtained when awell-known anhydrous aripiprazole is heated at the specific temperature.Further, the present inventors have found that the desired anhydrousaripiprazole crystals can be obtained from recrystallization of awell-known anhydrous aripiprazole by using the specific solvents.Moreover, the present inventors found that the desired anhydrousaripiprazole crystals can be obtained by suspending a well-knownanhydrous aripiprazole in the specific solvent, and heating thusobtained suspension.

The present invention thus completed on the basis of these findings andknowledge.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a thermogravimetric/differential thermogram of theAripiprazole Hydrate A obtained in Example 1.

FIG. 2 shows the ¹H-NMR spectrum (DMSO-de, TMS) of the AripiprazoleHydrate A obtained in Example 1.

FIG. 3 is a powder x-ray diffraction diagram of the Aripiprazole HydrateA obtained in Example 1.

FIG. 4 shows the ¹H-NMR spectrum (DMSO-d₆, TMS) of the AnhydrousAripiprazole Crystals B obtained in Example 2.

FIG. 5 is a powder x-ray diffraction diagram of the AnhydrousAripiprazole Crystals B obtained in Example 2.

FIG. 6 is a thermogravimetric/differential thermogram of thearipiprazole hydrate obtained in Reference Example 3.

FIG. 7 is a powder x-ray diffraction diagram of the aripiprazole hydrateobtained in Reference Example 3.

FIG. 8 shows thermogravimetric/differential thermal analysis endothermiccurve of the type C crystals of anhydrous aripiprazole obtained inExample 11.

FIG. 9 shows an H-NMR spectrum (DMSO-d₆, TMS) of the type C crystals ofanhydrous aripiprazole obtained in Example 11.

FIG. 10 shows a powder X-ray diffraction spectrum of the type C crystalsof anhydrous aripiprazole obtained in Example 11.

FIG. 11 shows an IR spectrum of the type C crystals of anhydrousaripiprazole obtained in Example 11.

FIG. 12 shows a solid ¹³C-NMR spectrum of the type C crystals ofanhydrous aripiprazole obtained in Example 11.

FIG. 13 shows a thermogravimetric/differential thermal analysisendothermic curve of the type D crystals of anhydrous aripiprazoleobtained in Example 12 or Example 13.

FIG. 14 shows an ¹H-NMR spectrum (DMSO-d₆, TMS) of the type D crystalsof anhydrous aripiprazole obtained in Example 12 or Example 13.

FIG. 15 shows a powder X-ray diffraction spectrum of the type D crystalsof anhydrous aripiprazole obtained in Example 12 or Example 13.

FIG. 16 shows an IR spectrum of the type D crystals of anhydrousaripiprazole obtained in Example 12 or Example 13.

FIG. 17 shows a solid ¹³C-NMR spectrum of the type D crystals ofanhydrous aripiprazole obtained in Example 12 or Example 13.

FIG. 18 shows a thermogravimetric/differential thermal analysisendothermic curve of the type E crystals of anhydrous aripiprazoleobtained in Example 14.

FIG. 19 shows an ¹H-NMR spectrum (DMSO-d₆, TMS) of the type E crystalsof anhydrous aripiprazole obtained in Example 14.

FIG. 20 shows a powder X-ray diffraction spectrum of the type E crystalsof anhydrous aripiprazole obtained in Example 14.

FIG. 21 shows an IR spectrum of the type E crystals of anhydrousaripiprazole obtained in Example 14.

FIG. 22 shows a thermogravimetric/differential thermal analysisendothermic curve of the type F crystals of anhydrous aripiprazoleobtained in Example 15.

FIG. 23 shows an ¹H-NMR spectrum (DMSO-ds, TMS) of the type F crystalsof anhydrous aripiprazole obtained in Example 15.

FIG. 24 shows a powder X-ray diffraction spectrum of the type F crystalsof anhydrous aripiprazole obtained in Example 15.

FIG. 25 shows an IR spectrum of the type F crystals of anhydrousaripiprazole obtained in Example 15.

FIG. 26 shows thermogravimetric/differential thermal analysisendothermic curve of the type G crystals of anhydrous aripiprazoleobtained in Example 16-b).

FIG. 27 shows an ¹H-NMR spectrum (DMSO-d₆, TMS) of the type G crystalsof anhydrous aripiprazole obtained in Example 16-b).

FIG. 28 shows a powder X-ray diffraction spectrum of the type G crystalsof anhydrous aripiprazole obtained in Example 16-b).

FIG. 29 shows an IR spectrum of the type G crystals of anhydrousaripiprazole obtained in Example 16-b).

FIG. 30 shows a thermogravimetric/differential thermal analysisendothermic curve of the glass form of anhydrous aripiprazole obtainedin Example 16-a).

FIG. 31 shows a powder X-ray diffraction spectrum of the glassy state ofanhydrous aripiprazole obtained in Example 16-a).

DETAILED DESCRIPTION OF THE INVENTION

According to first embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa powder x-ray diffraction spectrum which is substantially the same asthe powder x-ray diffraction spectrum shown in FIG. 3.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate haspowder x-ray diffraction characteristic peaks at 2θ=12.6°, 15.4°, 17.3°,18.0°, 18.6°, 22.50 and 24.8°.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasparticular infrared absorption bands at 2951, 2822, 1692, 1577, 1447,1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasan ¹H-NMR spectrum which is substantially the same as the H-NMR spectrum(DMSO-d₆, TMS) shown in FIG. 2.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasan ¹H-NMR spectrum (DMSO-d₆, TMS) having characteristic peaks at1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasan endothermic curve which is substantially the same as thethermogravimetric/differential thermal analysis (heating rate 5° C./min)endothermic curve shown in FIG. 1.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size of 50 μm or less.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size of 40 μm or less.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size of 35 μm or less.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size of 30 μm or less.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size of 25 μm or less.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size of 20 μm or less.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size range of 40 to 10 μm.

According to another embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size range of 36 to 14 μm.

According to a second aspect of the present invention is provided aprocess for the preparation of Hydrate A wherein said process comprisesthe steps of milling Conventional Hydrate.

According to a first embodiment of the second aspect of the presentinvention is provided a process for the preparation of Hydrate Acomprising the steps of milling Conventional Hydrate wherein saidmilling is performed by a milling machine.

According to another embodiment of the second aspect of the presentinvention is provided a process for the preparation of Hydrate Acomprising the steps of milling Conventional Hydrate wherein saidmilling machine is an atomizer, pin mill, jet mill or ball mill.

According to another embodiment of the second aspect of the presentinvention is provided a process for the preparation of Hydrate Acomprising the steps of milling Conventional Hydrate wherein saidmilling machine is an atomizer.

According to another embodiment of the second aspect of the presentinvention is provided a process for the preparation of Hydrate Acomprising the steps of milling Conventional Hydrate wherein saidmilling machine is an atomizer using a rotational speed of 5000-15000rpm for the main axis, a feed rotation of 10-30 rpm and a screen holesize of 1-5 mm.

According to various embodiments of a third aspect of the presentinvention is provided Hydrate A defined according to one or more of theembodiments described herein wherein said Hydrate is made by a processas described herein.

According to a fourth aspect of the present invention is providedaripiprazole drug substance of low hygroscopicity.

According to a first embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said low hygroscopicity is a moisture content of 0.5% or lessafter placing said drug substance for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humidity level of 100%.

According to a first embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said low hygroscopicity is a moisture content of 0.4% or lessafter placing said drug substance for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humidity level of 100%.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said low hygroscopicity is a moisture content of 0.25% or lessafter placing said drug substance for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humidity level of 100%.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said low hygroscopicity is a moisture content of 0.15% or lessafter placing said drug substance for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humidity level of 100%.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said low hygroscopicity is a moisture content of 0.10% or lessafter placing said drug substance for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humidity level of 100%.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said low hygroscopicity is a moisture content of 0.05% or lessafter placing said drug substance for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humidity level of 100%.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said low hygroscopicity is a moisture content of 0.04% or lessafter placing said drug substance for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humidity level of 100%.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance is Anhydrous Aripiprazole Crystals B asdefined herein.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance has a powder x-ray diffraction spectrumwhich is substantially the same as the powder x-ray diffraction spectrumshown in FIG. 5.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance has a powder x-ray diffraction spectrumhaving characteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance has particular infrared absorption bands at2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm⁻¹ on the IR(KBr) spectrum.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance has an ¹H-NMR spectrum which issubstantially the same as the ¹H-NMR spectrum (DMSO-d₆, TMS) shown inFIG. 4.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance has an ¹H-NMR spectrum (DMSO-d₆, TMS) havingcharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance exhibits an endothermic peak near about141.5° C. in thermogravimetric/differential thermal analysis (heatingrate 5° C./min).

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance exhibits an endothermic peak near about140.7° C. in differential scanning calorimetry (heating rate 5° C./min).

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance is Anhydrous Aripiprazole Crystals B andwill not substantially convert to a hydrous form of aripiprazole whenproperly stored even for an extended period. For instance, saidAnhydrous Aripiprazole Crystals B can be stored under a relativehumidity (RH) of 60% and at a temperature of 25° C., even for a periodnot less than 1 year.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance is Anhydrous Aripiprazole Crystals B andwill not substantially convert to a hydrous form of aripiprazole whenproperly stored even for an extended period. For instance, saidAnhydrous Aripiprazole Crystals B can be stored under a relativehumidity (RH) of 60% and at a temperature of 25° C., even for a periodnot less than 4 years.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance is Anhydrous Aripiprazole Crystals B andwill not substantially convert to a hydrous form of aripiprazole whenproperly stored even for a period not less than 0.5 year under arelative humidity (RH) of 75% and at a temperature of 40° C.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance has a mean size of 50 μm or less when smallparticle size is required for the formulation such as Tablet and othersolid dose formulations including for example flashmelt formulations.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance has a mean size of 40 μm or less if smallparticle size is required for the formulation such as Tablet and othersolid dose formulations including for example flashmelt formulations.

According to another embodiment of the fourth aspect of the presentinvention is provided aripiprazole drug substance of low hygroscopicitywherein said drug substance has a mean size of 30 μm or less if smallparticle size is required for formulation such as Tablet and other soliddose formulations including for example flashmelt formulations.

According to a fifth aspect of the present invention is provided aprocess for the preparation of Anhydrous Aripiprazole Crystals B.

According to a first embodiment of the fifth aspect of the presentinvention is provided a process for the preparation of AnhydrousAripiprazole Crystals B wherein said process comprises heatingAripiprazole Hydrate A.

According to a first embodiment of the fifth aspect of the presentinvention is provided a process for the preparation of AnhydrousAripiprazole Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 90-125° C. for about 3-50 hours.

According to another embodiment of the fifth aspect of the presentinvention is provided a process for the preparation of AnhydrousAripiprazole Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 100° C. for about 18 hours.

According to another embodiment of the fifth aspect of the presentinvention is provided a process for the preparation of AnhydrousAripiprazole Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 100° C. for about 24 hours.

According to another embodiment of the fifth aspect of the presentinvention is provided a process for the preparation of AnhydrousAripiprazole Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 120° C. for about 3 hours.

According to another embodiment of the fifth aspect of the presentinvention is provided a process for the preparation of AnhydrousAripiprazole Crystals B wherein said process comprises heatingAripiprazole Hydrate A for about 18 hours at 100° C. followed byadditional heating for about 3 hours at 120° C.

According to a sixth aspect of the present invention is providedAnhydrous Aripiprazole Crystals B defined according to one or more ofthe embodiments described herein and made by a process as providedherein.

According to a seventh aspect of the present invention is providedAnhydrous Aripiprazole Crystals B formulated with one or morepharmaceutically acceptable carriers.

Other embodiments of the present invention may comprise suitablecombinations of two or more of the embodiments and/or aspects disclosedherein.

Yet other embodiments and aspects of the invention will be apparentaccording to the description provided below.

Yet another aspect of the present invention comprised discovering thatwhen aripiprazole hydrate (Conventional Hydrate as defined herein) ismilled, it converts to an aripiprazole hydrate (Hydrate A as definedherein) with a different powder x-ray diffraction spectrum by differentpeak intensities. Moreover, it was found that Hydrate A loses the sharpdehydration endothermic peak of 123.5° C. which characterizes unmilledConventional Hydrate in thermogravimetric/differential thermal analysis.Thus, the Conventional Hydrate is transformed into Hydrate A aftermilling Conventional Hydrate and exhibits a gradual dehydrationendothermic peak between about 60° C. and 120° C. with a weak peak atabout 71° C.

Yet another aspect of the invention comprised discovering that whenheated to a specific temperature of 90-125° C. for 3-50 hr, this novelaripiprazole hydrate dehydrates gradually avoiding the aggregationphenomenon thought to be caused in conventional aripiprazole hydrate byrapid dehydration, and that anhydrous aripiprazole crystals obtained byheating of the novel aripiprazole hydrate to a specific temperature areanhydrous aripiprazole crystals with the desired properties.

Characterization of Hydrate A

Particles of “Hydrate A” as used herein have the physicochemicalproperties given in (1)-(5) below:

(1) It has an endothermic curve which is substantially the same as thethermogravimetric/differential thermal analysis (heating rate 5° C./min)endothermic curve shown in FIG. 1. Specifically, it is characterized bythe appearance of a small peak at about 71° C. and a gradual endothermicpeak around 60° C. to 120° C.

(2) It has an ¹H-NMR spectrum which is substantially the same as theH-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 2. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.1.7 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(3) It has a powder z-ray diffraction spectrum which is substantiallythe same as the powder x-ray diffraction spectrum shown in FIG. 3.Specifically, it has characteristic peaks at 2θ=12.6°, 15.40°, 17.3°,18.0°, 18.6°, 22.5° and 24.8°.

(4) It has clear infrared absorption bands at 2951, 2822, 1692, 1577,1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

(5) It has a mean particle size of 50 μm or less.

Process for Manufacturing Hydrate A

Hydrate A is manufactured by milling Conventional Hydrate. Conventionalmilling methods can be used to mill Conventional Hydrate. For example,Conventional Hydrate can be milled in a milling machine. A widely usedmilling machine can be used, such as an atomizer, pin mill, jet mill orball mill. Of these, the atomizer is preferred.

Regarding the specific milling conditions when using an atomizer, arotational speed of 5000-15000 rpm could be used for the main axis, forexample, with a feed rotation of 10-30 rpm and a screen hole size of 1-5mm.

The mean particle size of the Aripiprazole Hydrate A obtained by millingshould normally be 50 μm or less, preferably 30 μm or less. Meanparticle size can be ascertained by the particle size measurement methoddescribed hereinafter.

Characterization of Anhydrous Aripiprazole Crystals B

“Anhydrous Aripiprazole Crystals B” of the present invention as usedherein have the physicochemical properties given in (6)-(12) below.

(6) They have an ¹H-NMR spectrum which is substantially the same as the¹H-NMR spectrum (DMSO-ds, TMS) shown in FIG. 4. Specifically, they havecharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(7) They have a powder x-ray diffraction spectrum which is substantiallythe same as the powder x-ray diffraction spectrum shown in FIG. 5.Specifically, they have characteristic peaks at 2θ=11.0°, 16.6°, 19.3°,20.3° and 22.1°.

(8) They have clear infrared absorption bands at 2945, 2812, 1678, 1627,1448, 1377, 1173, 960 and 779 cm⁻¹ on the IR (KBr) spectrum.

(9) They exhibit an endothermic peak near about 141.5° C. inthermogravimetric/differential thermal analysis (heating rate 5°C./min).

(10) They exhibit an endothermic peak near about 140.7° C. indifferential scanning calorimetry (heating rate 5° C./min).

(11) Anhydrous Aripiprazole Crystals B of the present invention have lowhygroscopicity. For example, Anhydrous Aripiprazole Crystals B of thepresent invention maintain a water content of 0.4% or less after 24hours inside a dessicator set at a temperature of 60° C. and a humidityof 100%. Well-known methods of measuring water content can be used aslong as they are methods commonly used for measuring the water contentof crystals. For example, a method such as the Karl Fischer method canbe used.

(12) When the small particle size is required for the formulation suchas tablet and other solid dose formulations including for exampleflashmelt formulations, the mean particle size is preferably 50 μm orless.

Process for Manufacturing Anhydrous Aripiprazole Crystals B

In case of the formulation for which small particle size (less than 50μm) is required, the milling is necessary for the preparation. However,when a large amount of Conventional Anhydrous Aripiprazole or AnhydrousAripiprazole Crystals B having large particle size is milled, the milledsubstances adhere with each other in the milling machine. Accordingly,there is a disadvantage that it is difficult to industrially prepareAnhydrous Aripiprazole Crystals B having small particle size.

Under the circumstances, the inventors of the present invention havefound that Conventional hydrate can be easily milled, and AnhydrousAripiprazole Crystals B having small particle size can be obtained inhigh yield with good-operability by heating the milled hydrate A thusobtained.

The Anhydrous Aripiprazole Crystals B of the present invention areprepared for example by heating the aforementioned Aripiprazole HydrateA at 90-125° C. The heating time is generally about 3-50 hours, butcannot be stated unconditionally since it differs depending on heatingtemperature. The heating time and heating temperature are inverselyrelated, so that for example the heating time will be longer the lowerthe heating temperature, and shorter the higher the heating temperature.Specifically, if the heating temperature of Aripiprazole Hydrate A is100° C., the heating time should normally be 18 hours or more orpreferably about 24 hours. If the heating temperature of AripiprazoleHydrate A is 120° C., on the other hand, the heating time can be about 3hours. The Anhydrous Aripiprazole Crystals B of the present inventioncan be prepared with certainty by heating Aripiprazole Hydrate A forabout 1.8 hours at 100° C., and then heating it for about 3 hours at120° C. The Anhydrous Aripiprazole Crystals B of the present inventioncan also be obtained if the heating time is extended still further, butthis may not be economical.

When small particle size is not required for the formulation, e.g., whendrug substance is being manufactured for injectable or oral solutionformulations, Anhydrous Aripiprazole Crystal B can be also obtained thefollowing process.

The inventors also discovered that it is possible to obtain anhydrousaripiprazole crystals by heating conventional aripiprazole hydrate orconventional anhydrous aripiprazole crystals to a specific temperaturebut this process does not yield Anhydrous Aripiprazole Crystal Bcrystalline substance suitable for commercial use in the formulation ofsolid oral dose formulations.

Furthermore, the Anhydrous Aripiprazole Crystals 8 of the presentinvention are prepared for example by heating conventional anhydrousaripiprazole crystals at 90-125° C. The heating time is generally about3-50 hours, but cannot be stated unconditionally since it differsdepending on heating temperature. The heating time and heatingtemperature are inversely related, so that for example the heating timewill be longer the lower the heating temperature, and shorter the higherthe heating temperature.

Specifically, if the heating temperature of the anhydrous aripiprazolecrystals is 100° C., the heating time can be about 4 hours, and if theheating temperature is 120° C. the heating time can be about 3 hours.

In addition to Aripiprazole Hydrate A and Anhydrous AripiprazoleCrystals B mentioned above, the present invention provides AnhydrousAripiprazole Crystals C to G as follows.

1. The present invention relates to anhydrous aripiprazole crystals(hereinafter referred to as “type C crystals of anhydrous aripiprazole”)having the following physicochemical properties (1) to (5):

(1) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 8;

(2) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 9;

(3) a powder X-ray diffraction spectrum which is substantially identicalto the powder X-ray diffraction spectrum shown in FIG. 10;

(4) an IR spectrum which is substantially identical to the IR (KBr)shown in FIG. 11; and

(5) a solid ¹³C-NMR spectrum which is substantially identical to thesolid ¹³C-NMR spectrum shown in FIG. 12.

2. The present invention relates to anhydrous aripiprazole crystals(hereinafter referred to as “type D crystals of anhydrous aripiprazole”)having the following physicochemical properties (6) to (10):

(6) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 13;

(7) an ¹H-NMR spectrum which is substantially identical to the ³H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 14;

(8) a powder X-ray diffraction spectrum which is substantially identicalto the powder X-ray diffraction spectrum shown in FIG. 15;

(9) an IR spectrum which is substantially identical to the IR (KBr)shown in FIG. 16; and

(10) a solid ¹³C-NMR spectrum which is substantially identical to the¹³C-NMR spectrum shown in FIG. 17.

3. The present invention relates to anhydrous aripiprazole crystals(hereinafter referred to as “type E crystals of anhydrous aripiprazole”)having the following physicochemical properties (11) to (14):

(11) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 18;

(12) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 19;

(13) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 20; and

(14) an IR spectrum which is substantially identical to the IR (KBr)shown in FIG. 21.

4. The present invention relates to anhydrous aripiprazole crystals(hereinafter referred to as “type F crystals of anhydrous aripiprazole”)having the following physicochemical properties (15) to (18):

(15) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 22;

(16) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 23;

(17) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 24; and

(18) an IR spectrum which is substantially identical to the IR (KBr)shown in FIG. 25.

5. The present invention relates a process for preparing anhydrousaripiprazole crystals stated in the aforementioned item 1, characterizedby heating anhydrous aripiprazole crystals at a temperature being higherthan 140° C. and lower than 150° C.

6. The present invention relates a process for preparing anhydrousaripiprazole crystals stated in the aforementioned item 2, characterizedby recrystallizing from toluene.

7. The present invention relates to a process for preparing anhydrousaripiprazole crystals stated in the aforementioned item 3, characterizedby heating and dissolving anhydrous aripiprazole crystals inacetonitrile, and cooling it.

8. The present invention relates to a process for preparing anhydrousaripiprazole crystals stated in the aforementioned item 4, characterizedby heating a suspension of anhydrous aripiprazole crystals in acetone.

9. The present invention relates to a pharmaceutical compositioncontaining at least one anhydrous aripiprazole crystals selected fromthe group consisting of the anhydrous aripiprazole crystals stated inthe aforementioned item 1, the anhydrous aripiprazole crystals stated inthe aforementioned item 2, the anhydrous aripiprazole crystals stated inthe aforementioned item 3, the anhydrous aripiprazole crystals stated inthe aforementioned item 4, and the anhydrous aripiprazole crystalsstated in the after-mentioned item 10, together with pharmaceuticallyacceptable carriers.

10. The present invention relates to anhydrous aripiprazole crystals(hereinafter referred to as “type G crystals of anhydrous aripiprazole”)having the following physicochemical properties (19) to (22):

(19) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate; 5°C./min.) endothermic curve shown FIG. 26.

(20) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 27.

(21) a power X-ray diffraction spectrum which is substantially identicalto the power X-ray diffraction spectrum shown in FIG. 28; and

(22) an IR spectrum which is substantially identical to the IR (Kbr)shown in FIG. 29.

11. The present invention relates to a process for preparing anhydrousaripiprazole crystals stated in the aforementioned item 10,characterized by putting glassy state of Anhydrous Aripiprazole in asealed vessel and keeping it at room temperature for at least 2 weeks.

12. The present invention relates to a process for the preparation ofgranules, characterized by wet granulating conventional AnhydrousAripiprazole Crystals or Anhydrous Aripiprazole Crystals B, C, D, E, For G, drying the obtained granules at 70 to 100° C. and sizing it, thendrying the sized granules at 70 to 100° C. again.

13. The present invention relates to a process for the pharmaceuticalsolid oral preparation, characterized by drying a pharmaceutical solidoral preparation comprising conventional Anhydrous Aripiprazole Crystalsor Anhydrous Aripiprazole Crystals B, C, D, E, F or G, and one or morepharmaceutically acceptable carriers at 70 to 100° C.

14. The present invention relates to a pharmaceutical solid oralpreparation comprising Anhydrous Aripiprazole Crystals B, C, D, E, F orG and one or more pharmaceutically acceptable carriers, wherein saidpharmaceutical solid oral preparation has at least one dissolution rateselected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

15. The present invention relates to a pharmaceutical solid oralpreparation having at least one dissolution rate selected from the groupconsisting 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.

16. The present invention relates to a pharmaceutical solid oralpreparation obtained by wet granulating conventional AnhydrousAripiprazole Crystals, drying the obtained granules at 70 to 100° C. andsizing it, then drying the sized granules at 70 to 100° C. again, andthe pharmaceutical solid oral preparation has at least one dissolutionrate selected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

17. The present invention relates to a pharmaceutical solid oralpreparation obtained by drying a pharmaceutical solid oral preparationcomprising conventional Anhydrous Aripiprazole Crystals and one or morepharmaceutically acceptable carriers at 70 to 100° C., and thepharmaceutical solid oral preparation has at least one dissolution rateselected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

18. The present invention relates to a process for the preparation ofgranules, characterized by wet granulating conventional AripiprazoleHydrate Crystals, drying the obtained granules at 70 to 100° C. andsizing it, then drying the sized granules at 70 to 100° C. again.

19. The present invention relates to a process for the pharmaceuticalsolid oral preparation, characterized by drying a pharmaceutical solidoral preparation comprising conventional Aripiprazole Hydrate Crystalsand one or more pharmaceutically acceptable carriers at 70 to 100° C.

20. The present invention relates to a pharmaceutical solid oralpreparation obtained by wet granulating conventional AripiprazoleHydrate Crystals, drying the obtained granules at 70 to 100° C. andsizing it, then drying the sized granules at 70 to 100° C. again, andthe pharmaceutical solid oral preparation has at least one dissolutionrate selected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

21. The present invention relates to a pharmaceutical solid oralpreparation obtained by drying a pharmaceutical solid oral preparationcomprising conventional Aripiprazole Hydrate Crystals and one or morepharmaceutically acceptable carriers at 70 to 100° C., and thepharmaceutical solid oral preparation has at least one dissolution rateselected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

The Type C to F crystals of anhydrous aripiprazole of the presentinvention correspond to the Type-III to VI crystals of anhydrousaripiprazole disclosed in JP-2001-348276.

Type C Crystals of Anhydrous Aripiprazole

Type C crystals of anhydrous aripiprazole of the present invention havethe following physicochemical properties (1) to (5):

-   -   (1) an endothermic curve which is substantially identical to the        thermogravimetric/differential thermal analysis (heating rate:        5° C./min.) endothermic curve shown in FIG. 8, more        particularly, it has an endothermic peak around 150.2° C.;

(2) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 9. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7, 4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 111), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H);

(3) a powder X-ray diffraction spectrum which is substantially identicalto the powder X-ray diffraction spectrum shown in FIG. 10. Specifically,it has characteristic peaks at 2θ=12.6°, 13.7°, 15.4°, 18.1°, 19.0°,20.6°, 23.5° and 26.4°;

(4) an IR spectrum which is substantially identical to the IR (KBr)spectrum shown in FIG. 11. Specifically, it has clear infraredabsorption bands at 2939, 2804, 1680, 1375 and 780 cm⁻¹; and

(5) a solid ¹³C-NMR spectrum which is substantially identical to thesolid ¹³C-NMR spectrum shown in FIG. 12, specifically, it hascharacteristic peaks at 32.8 ppm, 60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2ppm, 159.9 ppm and 1.75.2 ppm.

Preparation Method of Type C Crystals of Anhydrous Aripiprazole

Type C crystals of anhydrous aripiprazole of the present invention isprepared, for example by heating an anhydrous aripiprazole at atemperature of higher than 140° C. and lower than 150° C.

Anhydrous aripiprazole used as the raw material may be conventionalanhydrous aripiprazole crystals, for example, type-I crystals ofanhydrous aripiprazole, type-II crystals of anhydrous aripiprazolecrystals and the like, and these anhydrous aripiprazoles may be eitherpurified products or crude materials. Alternatively, type B crystals ofanhydrous aripiprazole, type D crystals of anhydrous aripiprazole, typeE crystals of anhydrous aripiprazole, type E crystals of anhydrousaripiprazole, or type G crystals of anhydrous aripiprazole beingprepared in the present invention can be used as the raw material ofanhydrous aripiprazole. These anhydrous aripiprazoles can be used singlyor in combination of at least 2 kinds thereof.

Heating temperature is generally higher than 140° C. and lower than 150°C., preferably at 142-148° C., and heating time is generally for 15minutes to 3 hours, preferably for 30 minutes to 1 hour.

When, an anhydrous aripiprazole is heated at the above-mentionedtemperature, then type C crystals of anhydrous aripiprazole are formed.

Thus obtained type C crystals of anhydrous aripiprazole can be isolatedand purified by well-known methods. For example, after heating theanhydrous aripiprazole at the above-mentioned temperature, and bycooling to a room temperature, then type C crystals of anhydrousaripiprazole, having 100% of purity can be obtained.

Type D Crystals of Anhydrous Aripiprazole

Type D crystals of anhydrous aripiprazole of the present invention havethe following physicochemical properties (6) to (10):

(6) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 13; more particularly, it hasan endothermic peak around 136.8° C. and 141.6° C.;

(7) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 14. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7, 4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H);

(8) a powder X-ray diffraction spectrum which is substantially identicalto the powder X-ray diffraction spectrum shown in FIG. 15. Specifically,it has characteristic peaks at 2θ=8.7°, 11.6°, 16.3°, 17.7°, 18.6°,20.3°, 23.4° and 25.0°;

(9) an IR spectrum which is substantially identical to the IR (KBr)spectrum shown in FIG. 16. Specifically, it has clear infraredabsorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm⁻¹; and

(10) a solid ¹³C-NMR spectrum which is substantially identical to thesolid ¹³C-NMR spectrum shown in FIG. 17, specifically, it hascharacteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4ppm, 158.4 ppm, and 174.1 ppm.

Preparation Method of Type D Crystals of Anhydrous Aripiprazole

Type D crystals of anhydrous aripiprazole of the present invention isprepared, for example, by recrystallization of anhydrous aripiprazolefrom toluene. Specifically, an anhydrous aripiprazole is added totoluene, further heated and dissolved, then thus obtained solution iscooled. By such procedures, type D crystals of anhydrous aripiprazole ofthe present invention is separated out as crystals in toluene.

Anhydrous aripiprazole to be used as the raw materials may beconventional anhydrous aripiprazole, for example type-I crystals ofanhydrous aripiprazole, type-II crystals of anhydrous aripiprazole andthe like, and these anhydrous aripiprazoles may be either purifiedproducts or crude materials. Alternatively, type B crystals of anhydrousaripiprazole, type C crystals of anhydrous aripiprazole, type E crystalsof anhydrous aripiprazole, type F crystals of anhydrous aripiprazole, ortype G crystals of anhydrous aripiprazole being prepared in the presentinvention can be used as the raw material for anhydrous aripiprazoles.These anhydrous aripiprazoles can be used singly or in combination of atleast 2 kinds thereof.

When the solution obtained by heating and dissolving is cooled, type Dcrystals of anhydrous aripiprazole may be added as a seed crystal tosaid solution. Further, the seed crystal may be formed by coolinggradually said solution being obtained by heating and dissolving. In thepresence of the seed crystal, type D crystals of anhydrous aripiprazolemay be separated out.

Thus separated out type D crystals of anhydrous aripiprazole can beisolated and purified in accordance with well-known methods. By suchprocedures, type D crystals of anhydrous aripiprazole, having the purityof 100% can be obtained.

Type E Crystals of Anhydrous Aripiprazole

Type E crystals of anhydrous aripiprazole of the present invention havethe following physicochemical properties (11) to (14):

(11) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 18, specifically, it has anendothermic peak around 146.5° C.;

(12) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 19. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7, 4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H);

(13) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 20.Specifically, it has characteristic peaks at 2θ=8.0°, 13.7°, 14.6°,17.6°, 22.5° and 24.0°; and

(14) an IR spectrum which is substantially identical to the IR (KBr)spectrum shown in FIG. 21. Specifically, it has clear infraredabsorption bands at 2943, 2817, 1686, 1377, 1202, 969 and 774 cm⁻¹.

Preparation Method of Type E Crystals of Anhydrous Aripiprazole

Type E crystals of anhydrous aripiprazole of the present invention isprepared, for example by recrystallization of the anhydrous aripiprazolefrom acetonitrile. Specifically, by adding a well-known anhydrousaripiprazole to acetonitrile, heating and dissolving, then the solutionthus obtained may be cooled. In accordance with such procedures, type Ecrystals of anhydrous aripiprazole of the present invention areseparated out in the acetonitrile.

When a conventional anhydrous aripiprazole is added to acetonitrile,type-I crystals of anhydrous aripiprazole, type-II crystals of anhydrousaripiprazole and type D crystals of anhydrous aripiprazole are separatedout, other than type E crystals of anhydrous aripiprazole. Platecrystals being separated out from the acetonitrile solution at 70° C.are type-I crystals, type-II crystals and type D crystals, while type Ecrystals are precipitated out as needle crystals. When the acetonitrilesolution after separated out of these crystals is heated again (forexample, heated at over 75° C.), the plate crystals (type-I crystals,type-II crystals and type D crystals) are quickly dissolved, on thecontrary, the needle form crystals (type E crystals) do not dissolved.Additionally, when the acetonitrile solution is cooled again, thenneedle form crystals (type E crystals) are further separated out aroundthe needle form crystals (type E crystals) previously precipitated asthe seed crystals. Thus, type E crystals of anhydrous aripiprazole canbe precipitated in the acetonitrile solution.

Anhydrous aripiprazoles used as the raw materials may be conventionalanhydrous aripiprazoles, for example any one of type-I crystals ofanhydrous aripiprazole and type-II crystals of anhydrous aripiprazoleand the like, and these anhydrous aripiprazoles may be either purifiedproducts or crude materials. Alternatively, type B crystals of anhydrousaripiprazole, type C crystals of anhydrous aripiprazole, type D crystalsof anhydrous aripiprazole, type F crystals of anhydrous aripiprazole, ortype G crystals of anhydrous aripiprazole can be used as the rawmaterials for anhydrous aripiprazoles. These anhydrous aripiprazoles canbe used singly or in combination of at least 2 kinds thereof.

When the acetonitrile solution obtained by heating (heating anddissolving) is cooled, the type E crystals of aripiprazole may be addedas a seed crystal to said solution. Further, the seed crystal may beformed by cooling gradually said acetonitrile solution which wasobtained by heating.

Thus separated out type E crystals of anhydrous aripiprazole can beisolated and purified in accordance with well-known methods. By suchprocedures, type E crystals of anhydrous aripiprazole, having the purityof 100% can be obtained.

Type F Crystals of Anhydrous Aripiprazole

Type F crystals of anhydrous aripiprazole of the present invention havethe following physicochemical properties (15) to (18):

(15) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 22, specifically, it has anendothermic peaks around 137.5° C. and 149.8° C.;

(16) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 23. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 211), 1.68-1.78 ppm (m, 211),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7, 4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H);

(17) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 24.Specifically, it has characteristic peaks at 2θ=11.3°, 13.3°, 15.4°,22.8°, 25.2° and 26.9°, and

(18) Having an IR spectrum which is substantially identical to the IR(KBr) spectrum shown in FIG. 25. Specifically, it has clear infraredabsorption bands at 2940, 2815, 1679, 1383, 1273, 1177, 1035, 963 and790 cm⁻¹.

Preparation Method of Type F Crystals of Anhydrous Aripiprazole

Type F crystals of anhydrous aripiprazole of the present invention isprepared, for example by suspending an anhydrous aripiprazole inacetone, and thus obtained acetone suspension is heated.

Anhydrous aripiprazoles used as the raw materials may be conventionalanhydrous aripiprazole, for example any one of type-I crystals ofanhydrous aripiprazole and type-II crystals of anhydrous aripiprazoleand the like, and these anhydrous aripiprazoles may be either purifiedproducts or crude materials. Alternatively, type B crystals of anhydrousaripiprazole, type C crystals of anhydrous aripiprazole, type D crystalsof anhydrous aripiprazole, type E crystals of anhydrous aripiprazole, ortype G crystals of anhydrous aripiprazole prepared in the presentinvention can be used as the raw materials for anhydrous aripiprazoles.These anhydrous aripiprazoles can be used singly or in combination of atleast 2 kinds thereof.

Heating temperature of the acetone suspension may be generally about theboiling point of acetone, and heating time is generally 5 to 10 hours.When the acetone suspension is heated about the boiling point ofacetone, then type F crystals of anhydrous aripiprazole is formed, thecrystals are isolated by filtration with heating. Isolation of thecrystals may be carried out in accordance with well-known methods. Bysuch procedures, type F crystals of anhydrous aripiprazole, having thepurity of 100% can be obtained.

Type G Crystals of Anhydrous Aripiprazole

Type G crystals of anhydrous aripiprazole of the present invention havethe following physicochemical properties (19) to (22):

(19) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 26, more particularly, it hasan endothermic peak around 141.0° C. and an exothermic peak around122.7*C;

(20) an ¹H-NMR spectrum which is substantially identical to the ¹H-NMRspectrum (DMSO-d₆, TMS) shown in FIG. 27. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.49 ppm(dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 18), 7.11-7.17 ppm(m, 18), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H);

(21) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 28.Specifically, it has characteristic peaks at 2θ=10.1°, 12.8°, 15.2°,17.0°, 17.5°, 19.1°, 20.1°, 21.2°, 22.4°, 23.3°, 24.5° and 25.8°; and

(22) an IR spectrum which is substantially identical to the IR (KBr)spectrum shown in FIG. 29. Specifically, it has clear infraredabsorption bands at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787cm⁻¹.

Preparation Method of Type G Crystals of Anhydrous Aripiprazole

Type G crystals of anhydrous aripiprazole of the present invention canbe prepared, for example by putting glassy state of anhydrousaripiprazole in a sealed vessel and leaving to stand it at roomtemperature for at least two weeks, preferably two weeks to six months.Further, glassy state of anhydrous aripiprazole as starting material canbe obtained by heating and melting anhydrous aripiprazole at around 170°C., then cooling it to room temperature.

Anhydrous aripiprazole used as the raw material may be well-knownanhydrous aripiprazole crystals, for example, any one of type-I crystalsof anhydrous aripiprazole and type-II crystals of anhydrous aripiprazoleand the like, and these anhydrous aripiprazoles may be either purifiedproducts or crude materials. Alternatively, type B crystals of anhydrousaripiprazole, type C crystals of anhydrous aripiprazole, type D crystalsof anhydrous aripiprazole, type E crystals of anhydrous aripiprazole, ortype F crystals of anhydrous aripiprazole being prepared in the presentinvention can be used as the raw material of anhydrous aripiprazoles.These anhydrous aripiprazoles can be used singly or in combination of atleast 2 kinds thereof.

Thus obtained type G crystals of anhydrous aripiprazole can be isolatedand purified by well-known methods. For example, glassy state ofanhydrous aripiprazole leave to stand according to the above-mentionedmethod, then type G crystals of anhydrous aripiprazole, having 100% ofpurity can be obtained.

Type C crystals of anhydrous aripiprazole, type D crystals of anhydrousaripiprazole, type E crystals of anhydrous aripiprazole, type F crystalsof anhydrous aripiprazole and type G crystals of anhydrous aripiprazoleof the present invention neither easily convert into hydrates thereof,nor substantially decrease the original solubility, even when they arestored for a long period of time.

In accordance with the present invention, methods for preparinganhydrous aripiprazole crystals having high purity, which can apply inan industrial scale with a good repeatability is provided.

In accordance with the present invention, pharmaceutical compositionscomprising anhydrous aripiprazole crystals are provided, of which thesolubility does not decrease, and of which the stability can keepexcellent, even if they are stored for long time.

The anhydrous aripiprazole crystals which are the raw material forpreparing the Anhydrous Aripiprazole Crystals B to G of the presentinvention are prepared for example by Method a or b below.

“Method a”: Process for Preparing Crude Aripiprazole Crystals

Conventional Anhydrous Aripiprazole crystals are prepared by well-knownmethods, as described in Example 1 of Japanese Unexamined PatentPublication No. 191256/1990.

A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 gof sodium iodide with 600 ml of acetonitrile was refluxed for 30minutes. To this suspension was added 40 g of1-(2,3-dichlorophenyl)piperazine and 33 ml of triethylamine and thewhole mixture was further refluxed for 3 hours. After the solvent wasremoved by evaporation, the residue thus obtained was dissolved inchloroform, washed with water then dried with anhydrous magnesiumsulfate. The solvent was removed by evaporation, and the residue thusobtained was recrystallized from ethanol twice, to yield 57.1 g of7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydrocarbostyril.

Colorless flake crystals

Melting point: 139.0-139.5° C.

“Method b”: Process for Preparing Conventional Anhydrous Aripiprazole

The Method b is described in the Proceedings of the 4th Japanese-KoreanSymposium on Separation Technology (Oct. 6-8, 1996).

Furthermore, the Anhydrous Aripiprazole Crystals B of the presentinvention are prepared for example by heating conventional aripiprazolehydrate at 90-125° C. The heating time is generally about 3-50 hours,but cannot be stated unconditionally since it differs depending onheating temperature. The heating time and heating temperature areinversely related, so that for example the heating time will be longerthe lower the heating temperature, and shorter the higher the heatingtemperature. Specifically, if the heating temperature of thearipiprazole hydrate is 100° C., the heating time can be about 24 hours,while if the heating temperature is 120° C., the heating time can beabout 3 hours.

The aripiprazole hydrate which is the raw material for preparing theAnhydrous Aripiprazole Crystals B of the present invention is preparedfor example by Method c below.

“Method c”: Process for Preparing Conventional Hydrate

Aripiprazole hydrate is easily obtained by dissolving the anhydrousaripiprazole crystals obtained by Method a above in a hydrous solvent,and heating and then cooling the resulting solution. Using this method,aripiprazole hydrate is precipitated as crystals in the hydrous solvent.

An organic solvent containing water is usually used as the hydroussolvent. The organic solvent should be one which is miscible with water,such as for example an alcohol such as methanol, ethanol, propanol orisopropanol, a ketone such as acetone, an ether such as tetrahydrofuran,dimethylformamide, or a mixture thereof, with ethanol being particularlydesirable. The amount of water in the hydrous solvent can be 10-25% byvolume of the solvent, or preferably close to 20% by volume.

Medicinal Composition

A medicinal composition of the present invention will contain AnhydrousAripiprazole Crystals B, C, D, E, F and G in a pharmaceuticallyacceptable carrier or combination of carriers.

Carriers which are pharmaceutically acceptable include diluents andexcipients generally used in pharmaceuticals, such as fillers,extenders, binders, moisturizers, disintegrators, surfactants, andlubricants.

The medicinal composition of the present invention may be formulated asan ordinary medicinal preparation, for example in the form of tablets,flashmelt tablets, pills, powder, liquid, suspension, emulsion,granules, capsules, suppositories or as an injection (liquid,suspension, etc.).

When a tablet formulation is used, a wide variety of carriers that areknown in the field can be used. Examples include lactose, saccharose,sodium chloride, glucose, xylitol, mannitol, erythritol, sorbitol, urea,starch, calcium carbonate, kaolin, crystal cellulose, silic acid andother excipients; water, ethanol, propanol, simple syrup, glucoseliquid, starch liquid, gelatin solution, carbozymethyl cellulose,shellac, methyl cellulose, potassium phosphate, polyvinyl pyrolidone andother binders; dried starch, sodium alginate, agar powder, laminaranpowder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitanfatty acid esters, sodium lauryl sulfate, monoglyceride stearate,starch, lactose and other disintegrators; saccharose, stearin, cacaobutter, hydrogenated oil and other disintegration inhibitors; quaternaryammonium salt, sodium lauryl sulfate and other absorption promoters;glycerine, starch and other moisture retainers; starch, lactose, kaolin,bentonite, colloidal silic acid and other adsorbents; and refined talc,stearate, boric acid powder, polyethylene glycol and other lubricantsand the like. Tablets can also be formulated if necessary as tabletswith ordinary coatings, such as sugar-coated tablets, gelatin-coatedtablets, enteric coated tablets and film coated tablets, as well asdouble tablets and multilayered tablets.

When a pill formulation is used, a wide variety of carriers that areknown in the field can be used. Examples include glucose, lactose,starch, cacao butter, hardened vegetable oil, kaolin, talc and otherexcipients; gum arabic powder, traganth powder, gelatin, ethanol andother binders; and laminaran, agar and other disintegrators and thelike.

When a suppository formulation is used, a wide variety of carriers thatare known in the field can be used. Examples include polyethyleneglycol, cacao butter, higher alcohol, esters of higher alcohol, gelatinsemi-synthetic glyceride and the like.

Capsules are prepared according to ordinary methods by mixing anhydrousaripiprazole crystals with the various carriers described above andpacking them in hard gelatin capsules, soft capsules,hydroxypropylmethyl cellulose capsules (HPMC capsules) and the like.

In addition, colorants, preservatives, perfumes, flavorings, sweetenersand the like as well as other drugs may be included in the medicinalcomposition.

In case of forming the pharmaceutical solid oral preparation in the formof granules, it can be prepared by wet granulating a mixed powder ofgranulating ingredients comprising, anhydrous aripiprazole crystals(conventional anhydrous aripiprazole crystals or anhydrous aripiprazolecrystals selected from the group consisting of anhydrous aripiprazoletype B, C, D, E, F and G crystals) and various carriers which areheretofore well-known in this field, such as excipients, disintegrators,disintegration inhibitors, humectants, absorption accelerators,adsorbents, lubricants, colorants and the like (for the examples ofthese agents, those of previously mentioned can be referred to) byadding a liquid (generally, water or an aqueous solution containingbinding agents). As for the wet granulation, there are various methodsare included, for example, fluidized bed granulation, kneadinggranulation, extruding granulation, rotating granulation and the likecan be mentioned. Among these methods, in case of conducting thefluidized bed granulation, the granulating ingredients containingvarious carriers are mixed with inlet air, then upon continuedfluidizing the granulating ingredients and the liquid is sprayed toconduct granulation. In case of conducting the kneading granulation, thegranulating ingredients containing various carriers are mixed byagitation, then upon continued agitating the granulating ingredients,granulation is conducted by adding the liquid. After the granulation, ifnecessary, the obtained granules are sized to make them to the desiredsize by use of a suitable sieve or a mill having suitable screen size.The granules thus obtained by such a method are dried again in additionto usual drying being conducted when preparing the granules. As for thedrying methods, various methods can be applied, for example, methods byuse of a fluidized bed dryer, a fan dryer, a vacuum dryer and the likecan be mentioned. Generally, drying methods can be conducted underconventional conditions, for example, in case of using the fluidized beddryer, drying procedure is conducted with an air flow of 0.5 m₃/min to50 m³/min, an inlet air temperature at 70 to 100° C. for 10 min to 1hour. After dried, the granules are subjected to size, then furtherdried. In case of using the fluidized bed dryer or fan dryer or thelike, the drying procedure is conducted under the conditions with an airflow of 0.5 m³/min to 50 m³/min, an inlet air temperature at 70 to 100°C. for 1 to 6 hours. In case of using the vacuum dryer, the dryingprocedure is conducted under the conditions of reduced pressure of aboutat 0-10 torr of degree of vacuum at 70 to 100° C. of jacket temperaturefor 1 to 6 hour.

The thus prepared granules may be used as they are for thepharmaceutical solid oral preparations, or if necessary, they may beshaped in the form of tablets. Further, the dried granules dried byusual manner are shaped in the form of tablets, then they may be driedagain.

The thus prepared pharmaceutical solid oral preparation comprisinganhydrous aripiprazole crystals hardly changes to hydrates even if theyare stored for a long period of time, therefore the pharmaceutical solidoral preparation, of which dissolution rate does not hardly lowered(dissolution rate to maintain maximum drug concentration (Cmax): 60% orhigher dissolution rate obtained after 30 minutes at pH 4.5, 70%, orhigher dissolution rate obtained after 60 minutes at pH 4.5, or 55% orhigher dissolution rate obtained after 60 minutes at pH 5.0) can beprovided.

Another pharmaceutical solid oral preparation can be provided bygranulating a conventional aripiprazole hydrate crystals by a methodsimilar to that of mentioned above, and dried by usual manner undersimilar conditions, then dried again. Alternatively, the dried granulesdried by usual manner are shaped to tablets form, then they are driedagain, then pharmaceutical solid oral preparations of which dissolutionrate does not lowered (dissolution rate to maintain maximum drugconcentration (Cmax): 60% or higher dissolution rate obtained after 30minutes at pH 4.5, 70% or higher dissolution rate obtained after 60minutes at pH 4.5 or 55% or higher dissolution rate obtained after 60minutes at pH 5.0) can be provided. These facts can be understood that,the conventional anhydrous aripiprazole crystals or the aripiprazolehydrate crystals contained in the pharmaceutical solid oral preparationare changed to “B type crystals” of anhydrous aripiprazole by dryingtwice.

The amount of Anhydrous Aripiprazole Crystals B, C, D, E, F and G thatshould be included in the medicinal composition of the present inventioncan be selected from a wide range suitable for the indication sought tobe treated. Generally, the Anhydrous Aripiprazole Crystals B should bepresent in about 1-70% by weight or particularly about 1-30% by weightbased on the medicinal composition.

The method of administration of the medicinal composition of the presentinvention may be adjusted to suit, for example, the formulation of thedrug product, the age, gender and other conditions (including theseverity thereof) of the patient. In the case of tablets, pills,liquids, suspensions, emulsions, granules and capsules, for example,administration is oral. In the case of an injection, it is administeredintravenously either by itself or mixed with an ordinary replenishersuch as glucose or amino acids, or may also be administered by itselfintramuscularly, intracutaneously, subcutaneously or intraperitoneally,as necessary. In the case of a suppository, administration isintrarectal.

The dosage of the medicinal composition of the present invention isselected depending on the usage, the age, gender and other conditions ofthe patient, the severity of the condition and so forth, but ordinarilythe amount of anhydrous aripiprazole crystals can be about 0.1-10 mg per1 kg of body weight per day. The preparation which is the unit ofadministration should contain in the range of about 1-100 mg ofAnhydrous Aripiprazole Crystals B, more particularly 1-30 mg per unitdose.

The medicinal composition of the present invention is extremely stable,with substantially no decrease in solubility even when stored for longperiods of time.

The medicinal composition of the present invention is effective in theprevention and treatment of central nervous system disorders such asschizophrenia and may also be effective in the treatment of intractable(drug-resistant, chronic) schizophrenia with cognitive impairment andintractable (drug-resistant, chronic) schizophrenia without cognitiveimpairment, anxiety including mild anxiety, mania including bipolardisorder acute mania and acute mania, bipolar disorder, depressionincluding bipolar disorder depression, autism, Down's syndrome,attention deficit hyperactivity disorder (ADHD), Alzheimer's disease,Parkinson's disease and other neurodegenerative diseases, panic,obsessive compulsive disorder (OCD), sleep disorders, sexualdysfunction, alcohol and drug dependency, vomiting, motion sickness,obesity, miparticlee headache and cognitive impairment.

Analytical Methods

(1) The ¹H-NMR spectrum was measured in DMSO-de using TMS as thestandard.

(2) Powder X-ray Diffraction

Using a Rigaku Denki RAD-2B diffraction meter, the powder x-raydiffraction pattern was measured at room temperature using a Cu Kαfilled tube (35 kV 20 mA) as the x-ray source with a wide-anglegoniometer, a 1° scattering slit, an 0.15 mm light-intercepting slit, agraphite secondary monochromator and a scintillation counter. Datacollection was done in 2θ continuous scan mode at a scan speed of5°/minute in scan steps of 0.02° in the range of 3° to 40°.

(3) The IR spectrum was measured by the KBr method.

(4) Thermogravimetric/Differential Thermal Analysis

Thermogravimetric/differential thermal analysis was performed using aSeiko SSC 5200 control unit and a TG/DTA 220 simultaneous differentialthermal/thermogravimetric measurement unit. 5-10 mg samples were placedin open aluminum pans and heated from 20° C. to 200° C. in a drynitrogen atmosphere at a heating rate of 5° C./minute. α-alumina wasused as the standard substance.

(5) Differential Scanning Calorimetry

Thermogravimetric/differential thermal analysis was performed using aSeiko SSC 5200 control unit and a DSC 220C differential scanningcalorimeter. 5-10 mg samples were placed in crimped aluminum pans andheated from 20° C. to 200° C. in a dry nitrogen atmosphere at a heatingrate of 5° C./minute. α-alumina was used as the standard substance.

(6) Particle Size Measurement

0.1 g of the particles to be measured were suspended in a 20 ml n-hexanesolution of 0.5 g soy lecithin, and particle size was measured using asize distribution meter (Microtrack HPA, Microtrack Co.).

(7) Hygroscopicity Test Method

One g of the sample was accurately weighed in a weighing bottle(diameter 5 cm), covered with kimwipes and left to rest in a 60° C./100%RH environment (water/dessicator). 24 hours later, the weighing bottlewas removed, transferred to an environment of a room temperature andabout 30% RH (magnesium chloride hexahydrate saturated watersolution/dessicator) and left to rest for 24 hours and the water contentof the sample was measured by the Karl Fischer method.

(8) Solid ¹³C-NMR Spectrometry

Solid ¹³C-NMR spectrum was measured under the conditions as follows.

Measuring apparatus: CMX-360 Solid State NMR Spectrometer (manufacturedby Chemagnetic Inc.)

Computer: SPARC Station 2 (manufactured by SUN Microsystem, Inc.)

OS, Software: Solalis 1.1.1 Rev. B (Registered trademark: UNIX),Spinsight Ver. 2.5

Name of measured pulse: TOSS method (TOSS is a program name of theapparatus) among CP/MAS method.

Width of measured puls: 90° puls was used under the condition of CP.

Measuring sample tube: Test tube made of zirconia, having the outsidediameter of 7.5 mm, and inside capacity of 0.8 ml

Revolution: 4250 Hz (Revolution per second Contact time: 1 msec.

Waiting time: 20 sec.

Integrated times: 512 times

Measuring temperature: About 25° C. temperature of outside of test tube)

External standard: Methyl group (δ 17.3) of hexamethylbenzene was usedas the external standard.

The present invention is explained in more detail below using referenceexamples, examples, sample preparations and formulation examples.

Reference Example 1

19.4 g of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril and 16.2 g of1-(2,3-dichlorophenyl) piperadine 1 hydrochloride were added to 8.39 gof potassium carbonate dissolved in 140 ml of water, and circulated for3 hours under agitation. After reaction the mixture was cooled and theprecipitated crystals filtered out. These crystals were dissolved in 350ml of ethyl acetate, and about 210 ml of water/ethyl acetate azeotroperemoved under reflux. The remaining solution was cooled, and theprecipitated crystals filtered out. The resulting crystals were driedfor 14 hours at 60° C. to produce 20.4 g (74.2%) of raw aripiprazole.

30 g of the raw aripiprazole obtained above was recrystallized from 450ml of ethanol according to the methods described in Japanese UnexaminedPatent Publication No. 191256/1990, and the resulting crystals dried for40 hours at 80° C. to obtain anhydrous aripiprazole crystals. The yieldwas 29.4 g (98.0%).

The melting point (mp) of these anhydrous aripiprazole crystals was 140°C., matching the melting point of the anhydrous aripiprazole crystalsdescribed in Japanese Unexamined Patent Publication No. 191256/1990.

When these crystals were left for 24 hours in a dessicator set athumidity 100%, temperature 60° C., they exhibited hygroscopicity of 3.28(see Table 1 below).

Reference Example 2

6930 g of the intermediate raw aripiprazole obtained in ReferenceExample 1 was heat dissolved in 138 liters of hydrous ethanol (watercontent 20%) according to the method presented at the 4thJapanese-Korean Symposium on Separation Technology, gradually (2-3hours) cooled to room temperature, and then chilled to near 0° C. Theprecipitated crystals were filtered out, producing about 7200 g ofaripiprazole hydrate (wet state).

The wet-state aripiprazole hydrate crystals obtained above were driedfor 30 hours at 80° C. to obtain 6480 g (93.5%) of conventionalanhydrous aripiprazole crystals. The melting point (mp) of thesecrystals was 139.5° C. These crystals were confirmed by the Karl Fischermethod to be anhydrous, with a moisture value of 0.03%.

When left for 24 hours in a dessicator set at humidity 100%, temperature60° C., these crystals exhibited hygroscopicity of 1.78% (see Table 1below).

Reference Example 3

820 g of the intermediate wet-state aripiprazole hydrate obtained inReference Example 2 was dried for 2 hours at 50° C. to obtain 780 g ofaripiprazole hydrate crystals. These crystals had a moisture value of3.82% according to the Karl. Fischer method. As shown in FIG. 6,thermogravimetric/differential thermal analysis revealed endothermicpeaks at 75.0, 123.5 and 140.5° C. Because dehydration began near 70°C., there was no clear melting point (mp).

As shown in FIG. 7, the powder x-ray diffraction spectrum ofaripiprazole hydrate obtained by this method exhibited characteristicpeaks at 2θ=12.6°, 15.1°, 17.4°, 18.2°, 18.7∪, 24.8° and 27.5°.

The powder x-ray diffraction spectrum of this aripiprazole hydrate wasidentical to the powder x-ray diffraction spectrum of aripiprazolehydrate presented at the 4th Joint Japanese-Korean Symposium onIsolation Technology.

Reference Example 4

Preparation of 15 mg tablets containing type I crystals of anhydrousaripiprazole obtained in Reference Example 2.

Type-I crystals of anhydrous aripiprazole (525 g), lactose (1,995 g),corn starch (350 g) and crystalline cellulose (350 g) were charged in afluidized bed granulating dryer (Flow coater FLO-5, manufactured byFREUND INDUSTRIAL CO., LTD.), and these granulating ingredients weremixed by fluidizing for about 3 minutes with an inlet air temperature at70° C. and air flow rate of 3 m³/min. Further, the granulatingingredients were upon continued fluidizing under the same condition andsprayed about 1,400 g of the aqueous solution to obtained wet granules.The wet granules were dried under inlet air at temperature at 80° C.,for about 15 minutes. The obtained dried granules contained 4.3% ofwater. (Yield: 99%). The dried granules were subjected to sizing bypassing to a sieve of 710 μm.

About 1% by weight of magnesium stearate was added to the sized granulesand mixed, then the granules were supplied to a tablet machine (Rotarysingle tablet press 12HUK: manufactured by KIKUSUI SEISAKUSHO CO.,LTD.), there were obtained tablets, each having 95 mg of weight.

Water content of the tablets was measured according to volumetrictitration method (Karl-Fischer method) described in water contentmeasuring method in Japanese Pharmacopoea or the electrical quantitytitration method.

Water Content Measuring Method:

Sample (0.1 to 0.5 g) (in case of a tablet, 1 tablet was used) wasweighed precisely, and the water content was measured by use of a watercontent measuring equipment.

Volumetric titration:

-   -   Automated water content measuring equipment    -   Model: KF-06 (manufacture by MITSUBISHI CHEMICAL CORP.)

Electrical quantity titration method:

-   -   Automated micro-water content measuring equipment        -   Model: AQ-7F (manufactured by HIRANUMA SANGYO CO., LTD.)        -   Automated water vaporization equipment Model: LE-20S            (manufactured by HIRANUMA SANGYO CO., LTD.)        -   Heating temperature: 165±10° C.        -   Nitrogen gas flow rate: about 150 ml/min.

Reference Example 5

Preparation of 15 mg tablets containing type B crystals of anhydrousaripiprazole

Type B crystals of anhydrous aripiprazole (4,500 g), lactose (17,100 g),corn starch (3,000 g) and crystalline cellulose (3,000 g) were chargedin a fluidized bed granulating dryer (NEW-MARUMERIZER Model: NQ-500,manufactured by FUJI PAUDAL CO., LTD.), and these granulatingingredients were mixed by fluidizing for about 3 minutes with an inletair temperature at 70° C., air flow rate of 10 to 15 m³/min. Further,the granulating ingredients were upon continued fluidizing under thesame condition, and sprayed about 12,000 g of 5% aqueous solution ofhydrozypropyl cellulose to obtained wet granules. The wet granules weredried under inlet air at temperature at 85° C., for about 28 minutes.The thus obtained dried granules contained 3.8% of water (measured bythe method according to Reference Example 4). (Yield: 96%). The driedgranules were subjected to sizing by passing to a sieve of 850 μm.

About 1% by weight of magnesium stearate was added to the sized granulesand mixed, then the granules were supplied to a tablet machine (Rotarysingle tablet press 12HUK: manufactured by KIKUSUI SEISAKUSHO CO.,LTD.), there were obtained tablets, each having 95 mg of weight.

Example 1

500.3 g of the aripiprazole hydrate crystals obtained in ReferenceExample 3 were milled using a sample mill (small atomizer). The mainaxis rotation rate was set to 12,000 rpm and the feed rotation rate to17 rpm, and a 1.0 mm herringbone screen was used. Milling was completedin 3 minutes, resulting in 474.6 g (94.9%) of Aripiprazole Hydrate Apowder.

The Aripiprazole Hydrate A (powder) obtained in this way had a meanparticle size of 20-25 μm. The melting point (mp) was undeterminedbecause dehydration was observed beginning near 70° C.

The Aripiprazole Hydrate A (powder) obtained above exhibited an H-NMR(DMSO-d₆, TMS) spectrum which was substantially the same as the H-NMRspectrum shown in FIG. 2. Specifically, it had characteristic peaks at1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The Aripiprazole Hydrate A (powder) obtained above had a powder x-raydiffraction spectrum which was substantially the same as the powderx-ray diffraction spectrum shown in FIG. 3. Specifically, it hadcharacteristic peaks at 2θ=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and24.8°. This pattern is different from the powder x-ray spectrum ofunmilled aripiprazole hydrate shown in FIG. 7.

The Aripiprazole Hydrate A (powder) obtained above had infraredabsorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and784 cm⁻¹ on the IR (KBr) spectrum.

As shown in FIG. 1, the Aripiprazole Hydrate A (powder) obtained abovehad a weak peak at 71.3° C. in thermogravimetric/differential thermalanalysis and a broad endothermic peak (weight loss observedcorresponding to one water molecule) between 60-120° C.—clearlydifferent from the endothermic curve of unmilled aripiprazole hydrate(see FIG. 6).

Example 2

450 g of the Aripiprazole Hydrate A (powder) obtained in Example 1 wasdried for 24 hours at 100° C. using a hot air dryer to produce 427 g(yield 98.7%) of Anhydrous Aripiprazole Crystals B.

These Anhydrous Aripiprazole Crystals B had a melting point (mp) of139.7° C.

The Anhydrous Aripiprazole Crystals B obtained above had an ¹H-NMRspectrum (DMSO-d₆, TMS) which was substantially the same as the ¹H-NMRspectrum shown in FIG. 4. Specifically, they had characteristic peaks at1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The Anhydrous Aripiprazole Crystals B obtained above had a powder x-raydiffraction spectrum which was substantially the same as the powderx-ray diffraction spectrum shown in FIG. 5. Specifically, they hadcharacteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.

The Anhydrous Aripiprazole Crystals B obtained above had remarkableinfrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173,960 and 779 cm⁻¹ on the IR (KBr) spectrum.

The Anhydrous Aripiprazole Crystals B obtained above exhibited anendothermic peak near about 141.5° C. in thermogravimetric/differentialthermal analysis.

The Anhydrous Aripiprazole Crystals B obtained above exhibited anendothermic peak near about 140.7° C. in differential scanningcalorimetry.

Even when the Anhydrous Aripiprazole Crystals B obtained above were leftfor 24 hours in a dessicator set at humidity 100%, temperature 60° C.,they did not exhibit hygroscopicity exceeding 0.4% (See Table 1 below).

Example 3

44.29 kg of the Aripiprazole Hydrate A (powder) obtained in Example 1was dry heated for 18 hours in a 100° C. hot air dryer and then heatedfor 3 hours at 120° C. to produce 42.46 kg (yield 99.3%) of AnhydrousAripiprazole Crystals B.

The physicochemical properties of the resulting Anhydrous AripiprazoleCrystals B were the same as the physicochemical properties of theAnhydrous Aripiprazole Crystals B obtained in Example 2.

The Anhydrous Aripiprazole Crystals B obtained in this way did notexhibit hygroscopicity of more than 0.4% even when left for 24 hours ina dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 4

40.67 kg of the Aripiprazole Hydrate A (powder) obtained in Example 1was dry heated for 18 hours in a 100° C. hot air dryer and then heatedfor 3 hours at 120° C. to produce 38.95 kg (yield 99.6%) of AnhydrousAripiprazole Crystals B.

The physicochemical properties of the resulting Anhydrous AripiprazoleCrystals B were the same as the physicochemical properties of theAnhydrous Aripiprazole Crystals B obtained in Example 2.

The Anhydrous Aripiprazole Crystals B obtained in this way did notexhibit hygroscopicity of more than 0.4% even when left for 24 hours ina dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Examples 5-10 are useful for injectable or oral solution formulationsbut not solid dose formulations since they were made by heatingConventional Anhydrous Aripiprazole or Conventional Hydrate instead ofHydrate A.

Example 5

The hygroscopic anhydrous aripiprazole crystals obtained in ReferenceExample 1 were heated for 50 hours at 100° C. using the same methods asin Example 2. The physicochemical properties of the resulting AnhydrousAripiprazole Crystals B were the same as the physicochemical propertiesof the Anhydrous Aripiprazole Crystals B obtained in Example 2.

The Anhydrous Aripiprazole Crystals B obtained in this way did notexhibit hygroscopicity of more than 0.4% even when left for 24 hours ina dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 6

The hygroscopic anhydrous aripiprazole crystals obtained in ReferenceExample 1 were heated for 3 hours at 120° C. using the same methods asin Example 2. The physicochemical properties of the resulting AnhydrousAripiprazole Crystals B were the same as the physicochemical propertiesof the Anhydrous Aripiprazole Crystals B obtained in Example 2.

The Anhydrous Aripiprazole Crystals B obtained in this way did notexhibit hygroscopicity of more than 0.4% even when left for 24 hours ina dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 7

The hygroscopic anhydrous aripiprazole crystals obtained in ReferenceExample 2 were heated for 50 hours at 100° C. using the same methods asin Example 2. The physicochemical properties of the resulting AnhydrousAripiprazole Crystals B were the same as the physicochemical propertiesof the Anhydrous Aripiprazole Crystals B obtained in Example 2.

The Anhydrous Aripiprazole Crystals B obtained in this way did notexhibit hygroscopicity of more than 0.4% even when left for 24 hours ina dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 8

The hygroscopic anhydrous aripiprazole crystals obtained in ReferenceExample 2 were heated for 3 hours at 120° C. using the same methods asin Example 2. The physicochemical properties of the resulting AnhydrousAripiprazole Crystals B were the same as the physicochemical propertiesof the Anhydrous Aripiprazole Crystals B obtained in Example 2.

The Anhydrous Aripiprazole Crystals B obtained in this way did notexhibit hygroscopicity of more than 0.4% even when left for 24 hours ina dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 9

The aripiprazole hydrate crystals obtained in Reference Example 3 wereheated for 50 hours at 100° C. using the same methods as in Example 2.The physicochemical properties of the resulting Anhydrous AripiprazoleCrystals B were the same as the physicochemical properties of theAnhydrous Aripiprazole Crystals B obtained in Example 2.

The Anhydrous Aripiprazole Crystals B obtained in this way did notexhibit hygroscopicity of more than 0.4% even when left for 24 hours ina dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 10

The aripiprazole hydrate crystals obtained in Reference Example 3 wereheated for 3 hours at 120° C. using the same methods as in Example 2.The physicochemical properties of the resulting Anhydrous AripiprazoleCrystals B were the same as the physicochemical properties of theAnhydrous Aripiprazole Crystals B obtained in Example 2.

The Anhydrous Aripiprazole Crystals B obtained in this way exhibitedhygroscopicity of no more than 0.4% even when left for 24 hours in adessicator set at humidity 100%, temperature 60° C. (see Table 1 below).

Example 11 (Preparation of Type C Crystals of Anhydrous Aripiprazole)

100 Milligrams of type-I crystals of anhydrous aripiprazole obtained inReference Example 2 were heated about 145° C. (±3° C.). In thisoccasion, there was observed the phenomena that the crystals were oncemelted, then again crystallized. After that, 100 mg (yield: 100%) ofType C crystals of anhydrous aripiprazole were obtained. The meltingpoint of the crystals was 150° C. The crystals were colorless prismform.

The type C crystals of anhydrous aripiprazole obtained above had anendothermic curve which was substantially identical to the endothermiccurve of thermogravimetric/differential thermal analysis (heating rate:5° C./minute) shown in FIG. 8. Specifically, it showed the endothermiccurve around 150.2° C.

The type C crystals of anhydrous aripiprazole thus obtained exhibited an¹H-NMR spectrum (DMSO-d₆, TMS) which was substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 9. Specifically, it had thecharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H), and10.00 ppm (s, 1H).

The type C crystals of anhydrous aripiprazole obtained above had apowder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 10. Specifically, ithad the characteristic peaks at 2θ=12.6°, 13.7°, 15.4°, 18.1°, 19.0°,20.6°, 23.5° and 26.4°.

The type C crystals of anhydrous aripiprazole obtained above had an IRspectrum which was substantially identical to the IR (KBr) spectrumshown in FIG. 11. Specifically, it had the characteristic infraredabsorption bands at 2939, 2804, 1680, 1375 and 780 cm⁻¹.

The type C crystals of anhydrous aripiprazole obtained above exhibited asolid ¹³C-NMR spectrum, which was substantially identical to the solid¹³C-NMR spectrum shown in FIG. 12. Specifically, it had thecharacteristic peaks at 32.8 ppm, 60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2ppm, 159.9 ppm and 175.2 ppm.

According to the above-mentioned data on endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of thetype C crystals of anhydrous aripiprazole was confirmed.

When the type C crystals of anhydrous aripiprazole crystals obtainedabove were left for 24 hours in a dessicator where the conditions wereset at humidity 100%, and temperature 60° C., then the crystals did notexhibit hygroscopicity higher than 0.4% (see, Table 1 below).

Example 12 (Preparation of Type D Crystals of Anhydrous Aripiprazole)

The type-I crystals of anhydrous aripiprazole obtained in ReferenceExample 2 were added in 200 ml of toluene, and dissolved by heating at74° C. After confirmed that it was dissolved completely, the toluenesolution was cooled to 7° C., and the precipitated crystals werecollected by filtration. The crystals were subjected to air-drying asthey were so as to obtain 17.9 g (yield: 89.5%) of type D crystals ofanhydrous aripiprazole.

The type D crystals of anhydrous aripiprazole obtained above had anendothermic curve substantially identical to the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) shown in FIG. 13. Specifically, it had the endothermic peaksat about 136.8° C. and about 141.6°.

The type D crystals of anhydrous aripiprazole obtained above exhibited¹H-NMR spectrum (DMSO-d₆, TMS) which was substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 14. Specifically, they hadthe characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m,2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t,J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H),6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04ppm (d, J=8.1 Hz, 1H), 7.1.1-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H),and 10.00 ppm (s, 1H).

The type D crystals of anhydrous aripiprazole obtained above had apowder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 15. Specifically, ithad the characteristic peaks at 2θ=8.7°, 11.6°, 16.3°, 17.7°, 18.6°,20.3°, 23.4° and 25.0°.

The type D crystals of anhydrous aripiprazole obtained above had an IRspectrum which was substantially identical to the IR (KBr) spectrumshown in FIG. 16. Specifically, it had the characteristic infraredabsorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm⁻¹.

The type D crystals of anhydrous aripiprazole obtained above exhibited asolid ¹³C-NMR spectrum which was substantially identical to the solid¹³C-NMR spectrum shown in FIG. 17. Specifically, it had thecharacteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4ppm, 158.5 ppm and 174.1 ppm.

According to the above-mentioned data on the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of typeD crystals of anhydrous aripiprazole was confirmed.

When the type D crystals of anhydrous aripiprazole crystals obtainedabove were left for 24 hours in a dessicator where the conditions wereset at humidity 100%, and temperature 60° C., the crystals did not havehygroscopicity higher than 0.4% (see, Table 1 below).

Example 13 (Preparation of Type D Crystals of Anhydrous Aripiprazole)

1,200 Grams of the type-I crystals of anhydrous aripiprazole obtained inReference Example 2 were dissolved in 18 liters of toluene, withheating. This toluene solution was cooled to 40° C., and 36 g of type-Dcrystals of anhydrous aripiprazole obtained in Example 12 were added asseed crystals, then the solution was cooled to 10° C. and allowed tostand as it is. The precipitated crystals were collected by filtration,dried at 60° C. for 18 hours to obtain 1,073 g (yield: 86.8%) of type Dcrystals of anhydrous aripiprazole (purity: 100%). The crystals werecolorless plate form.

The type D crystals of anhydrous aripiprazole had an endothermic curvesubstantially identical to the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) shown in FIG. 13. Specifically, it had the endothermic peaksaround about 136.8° C. and about 141.6°.

The type D crystals of anhydrous aripiprazole obtained above exhibitedan ¹H-NMR spectrum (DMSO-d₆, TMS) which was substantially identical tothe ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 14. Specifically, ithad the characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m,2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t,J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H),6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H), and10.00 ppm (s, 1H).

The type D crystals of anhydrous aripiprazole obtained above had apowder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 15. Specifically, ithad the characteristic peaks at 2θ=8.7°, 11.6°, 16.3°, 17.7°, 18.6°,20.3°, 23.4° and 25.0°.

The type D crystals of anhydrous aripiprazole obtained above had an IRspectrum which was substantially identical to the IR (KBr) spectrumshown in FIG. 16. Specifically, it had characteristic infraredabsorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm⁻¹.

The type D crystals of anhydrous aripiprazole obtained above had a solid¹³C-NMR spectrum which was substantially identical to the solid ¹³C-NMRspectrum shown in FIG. 17. Specifically, it had the characteristic peaksat 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.5 ppm and174.1 ppm.

According to the above-mentioned data on the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of typeD crystals of anhydrous aripiprazole was confirmed.

When the type D crystals of anhydrous aripiprazole crystals obtainedabove were left for 24 hours in a dessicator where the conditions wereset at humidity 100%, and temperature 60° C., the crystals did notexhibit hygroscopicity higher than 0.40 (see, Table 1 below).

Example 14 (Preparation of Type E Crystals of Anhydrous Aripiprazole)

Grams of type-I crystals of anhydrous aripiprazole obtained in ReferenceExample 2 was dissolved in 1000 ml of acetonitrile with heating at 80°C. This acetonitrile solution was cooled to about 70° C. by taking forabout 10 minutes, and was kept at this temperature for about 30 minutesto precipitate the seed crystals. Next, the temperature of said solutionwas slowly risen to 75° C., and the crystals were grown up by keepingthis temperature for 1 hour. Then, the solution was cooled to 10° C. bytaking about 4 hours, and the precipitated crystals were collected byfiltration. Thus obtained crystals were subjected to air-dryingovernight, there were obtained 37.28 g (yield: 93.2%) of type E crystalsof anhydrous aripiprazole (purity: 100%). The melting point of thesecrystals was 145° C., and the crystals were colorless needle form.

The type E crystals of anhydrous aripiprazole had an endothermic curvesubstantially identical to the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) shown in FIG. 18. Specifically, it had endothermic peak atabout 146.5°.

The type E crystals of anhydrous aripiprazole obtained above exhibitedan ¹H-NMR spectrum (DMSO-d₆, TMS) which was substantially identical tothe ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 19. Specifically, ithad the characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m,2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t,J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H),6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H), and10.00 ppm (s, 1H).

The type E crystals of anhydrous aripiprazole obtained above had apowder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 20. Specifically, ithad the characteristic peaks at 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5° and24.0°.

The type E crystals of anhydrous aripiprazole obtained above had an IRspectrum which was substantially identical to the IR (KBr) spectrumshown in FIG. 21. Specifically, it had the characteristic infraredabsorption bands at 2943, 2817, 1686, 1377, 1202, 969 and 774 cm⁻¹.

According to the data on the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of typeE crystals of anhydrous aripiprazole was confirmed.

When the type E crystals of anhydrous aripiprazole obtained above wereleft for 24 hours in a dessicator where the conditions were set athumidity 100%, and temperature 60° C., the crystals did not exhibithygroscopicity higher than 0.4% (see, Table 1 below).

Example 15 (Preparation of Type F Crystals of Anhydrous Aripiprazole)

140 Grams of type-I crystals of anhydrous aripiprazole obtained inReference Example 2 were suspended in 980 ml of acetone and continued toreflux for 7.5 hours with stirring. Next, the suspension was filtered inhot condition, and crystals separated out were subjected to air-dryingfor 16 hours at room temperature, there was obtained 86.19 g (yield:61.6%) of type F crystals of anhydrous aripiprazole (purity: 100%). Thecrystals were colorless prism form.

The type F crystals of anhydrous aripiprazole had an endothermic curvesubstantially identical to the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) shown in FIG. 22. Specifically, it had the exothermic peaksat about 137.5° C. and about 149.8° C.

The type F crystals of anhydrous aripiprazole obtained above exhibitedan ¹H-NMR spectrum (DMSO-d₆, TMS) which was substantially identical tothe ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 23. Specifically, ithad the characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m,2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t,J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H),6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H), and10.00 ppm (s, 1H).

The type F crystals of anhydrous aripiprazole obtained above had apowder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 24. Specifically, ithad the characteristic peaks at 2θ-=11.3°, 13.3°, 15.40, 22.8°, 25.2°and 26.9°.

The type F crystals of anhydrous aripiprazole obtained above had an IRspectrum which was substantially identical to the IR (KBr) spectrumshown in FIG. 25. Specifically, it had the characteristic infraredabsorption bands at 2940, 2815, 1679, 1383, 1273, 1177, 1035, 963 and790 cm⁻;

According to the data on endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of typeF crystals of anhydrous aripiprazole was confirmed.

When the type F crystals of anhydrous aripiprazole crystals obtainedabove were left for 24 hours in a dessicator where the conditions wereset at humidity 100%, and temperature 60° C., the crystals did notexhibit hygroscopicity higher than 0.4% (see, Table 1 below).

TABLE 1 Initial Moisture Moisture Content Sample Content (%) After 24hrs (%) Refexence Example 1 0.04 3.28 Reference Example 2 0.04 1.78Example 2 0.04 0.04 Example 3 0.02 0.02 Example 4 0.02 0.02 Example 50.04 0.04 Example 6 0.04 0.04 Example 7 0.04 0.03 Example 8 0.04 0.03Example 7 0.03 0.01 Example 10 0.05 0.05 Example 11 0.03 0.03 Example 120.04 0.03 Example 13 0.04 0.03 Example 14 0.06 0.09 Example 15 0.04 0.04

Example 16

a) Type I crystals of anhydrous aripiprazole (10 g) obtained inReference Example 2 was charged in a stainless steel round tray(diameter: 80 mm), and heated to about 170° C. so as to meltedcompletely. When this melted liquid was cooled, then it solidifiedclarity with pale brawn in color, the solid was peeled off from thestainless steel round tray, there was obtained 9.8 g (yield: 98%) ofglassy state of anhydrous aripiprazole. The obtained glassy stateproduct was characterized by having no significant peak observed in apowder X-ray determination. (cf. FIG. 31).

According to the thermogravimetric/differential thermal analysis(heating rate: 5° C./minute), as shown in FIG. 30, an exothermic peak oftype B crystals of anhydrous aripiprazole was observed at around 86.5°C. While, an endothermic peak of type B crystals of anhydrousaripiprazole owing to melting was observed at around 140.1° C.

b) When the glassy state of anhydrous aripiprazole obtained in Example16-a) were charged in a sealed vessel and left to stand at roomtemperature for about 6 months, then type G crystals of anhydrousaripiprazole having white in color was obtained by changing the colorfrom pale brown (25 g, yield: 100%). Melting point: 138 to 139° C.

The type G crystals of anhydrous aripiprazole had an endothermic curvewhich was substantially identical to the thermogravimetric/differentialthermal analysis (heating rate: 5° C./min.) endothermic curve shown inFIG. 26, more particularly, it has an endothermic peak around 141.0° C.and an exothermic peak around 122.7° C.

The type G crystals of anhydrous aripiprazole obtained as aboveexhibited an ¹H-NMR spectrum which was substantially identical to theH-NMR spectrum (DMSO-ds, TMS) shown in FIG. 27. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, =2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

The type G crystals of anhydrous aripiprazole obtained as above had apowder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 28. Specifically, ithas characteristic peak at 2θ=10.1°, 12.8°, 15.2°, 17.0°, 17.5°, 19.1°,20.1°, 21.2°, 22.4°, 23.3°, 24.5° and 25.8°.

The type G crystals of anhydrous aripiprazole obtained above had an IRspectrum which was substantially identical to the IR (KBr) spectrumshown in FIG. 29. Specifically, it has clear infrared absorption bandsat 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787 cm⁻¹.

Example 17

a) Preparation of granules of 30 mg tablets containing type B crystalsof anhydrous aripiprazole for additional drying

Type B crystals of anhydrous aripiprazole (1,500 g), lactose (5,700 g),corn starch (1,000 g) and crystalline cellulose (1,000 g) were chargedin a fluidized bed granulating dryer (Flow Coater Model FLO-5M;manufactured by FROINT SANGYO KABUSHIKI KAISHA), and these granulatingingredients were mixed by fluidizing for about 3 minutes with an inletair temperature at 60° C., air flow rate of 3 to 4 m³/min. Further, thegranulating ingredients were continued fluidizing under the samecondition, and sprayed with about 4,000 g of 5, aqueous solution ofhydroxypropyl cellulose to obtain wet granules. The wet granules weredried under an inlet air temperature at 85° C., for about 20 minutes.The obtained dried granules contained 3.8% of water (measured by themethod according to Reference Example 4).

b) The dried granules (4 kg) obtained in Example 17-a) were sized by useof a mill (FIORE F-0: manufactured by TOKUJU CORPORATION).

The sized granules (3 kg) were charged in a fluidized bed granulatingdryer (Flow Coater Model FLO-5M; manufactured by FREUND INDUSTRIAL CO.,LTD.), and these granulating ingredients were dried under an inlet airtemperature at 85° C., and air flow rate of 2 m³/min for 2 hours. Theobtained dried granules contained 3.6% of water (measured by the methodaccording to Reference Example 4).

About 1% by weight of magnesium stearate was added to the sized granulesand mixed, then the granules were supplied to a tabletting machine (aRotary single tablet press, Model VIRGO: manufactured by KIKUSUISEISAKUSHO CO., LTD.), and there were obtained tablets, each having 190mg of weight.

c) The dried granules (3 kg) obtained in Example 17-a) were charged in avacuum dryer (vacuum granulating dryer model; VG-50: manufactured byKIKUSUI SEISAKUSHO CO., LTD.), and dried at 70° C. of a jackettemperature, under a reduced pressure at 5 torr of degree of vacuum for1 hour. The thus obtained dried granules contained 3.1% of water(measured by the method according to Reference Example 4). The driedgranules were subjected to sizing by passing to a sieve of 850 μm.

About 1% by weight of magnesium stearate was added to the sized granulesand mixed, then the granules were supplied to a tablet machine (Rotarysingle tablet press, Model VIRGO: manufactured by KIKUSUI SEISAKUSHOCO., LTD.), and there were obtained tablets, each having 190 mg ofweight.

Example 18

a) Preparation of 30 mg tablets containing type B crystals of anhydrousaripiprazole

Anhydrous aripiprazole (type B crystals) (4,500 g), lactose (17,100 g),corn starch (3,000 g) and crystalline cellulose (3,000 g) were chargedin a fluidized bed granulating dryer (NEW-MARUMERIZER Model: NQ-500,manufactured by FUJI PAUDAL CO., LTD.), and these granulatingingredients were mixed by fluidizing for about 3 minutes with an inletair temperature at 70° C., air flow rate of 10-15 m³/min. Further, thegranulating ingredients were continued fluidizing under the samecondition, and were sprayed with about 12,000 g of 5% aqueous solutionof hydroxypropyl cellulose to obtain wet granules. The wet granules weredried under inlet air at temperature of 85° C., for about 30 minutes.The obtained dried granules contained 3.6% of water (measured by themethod according to Reference Example 4). (Yield: 96%). The driedgranules were sized by passing to a mill (FIOLE F-0: manufactured byTOKUJU CORPORATION).

About 1% by weight of magnesium stearate was added to the sized granulesand mixed, then the granules were supplied to a tablet machine (a Rotarysingle tablet press, VIRGO: manufactured by KIKUSUI SEISAKUSHO CO.,LTD.), and there were obtained tablets, each having 190 mg of weight.

b) The tablets (5 kg) obtained in Example 18-a) were charged in a fandryer (AQUA COATER AQC-48T, manufactured by FREUND INDUSTRIAL CO.,LTD.), and dried under inlet air at temperature of 90° C., air flow rateof 2 m³/min for 6 hours. The obtained dried granules contained 3.3% ofwater (measured by the method according to Reference Example 4).c) The dried tablets (3 kg) obtained in Example 18-a) were charged in avacuum dryer (vacuum granulating dryer, VG-50: manufactured by KIKUSUISEISAKUSHO CO., LTD.), and dried at 80° C. of a jacket temperature,under reduced pressure of 5 torr of degree of vacuum for 4 hours. Theobtained dried tablets contained 2.7% of water (measured by the methodaccording to Reference Example 4).

Example 19

a) By the procedures similar to those of Example 18-a), there wereobtained tablets (containing type I crystals of anhydrous aripiprazoleobtained in Reference Example 2), each having 190 mg of weight,b) The tablets were dried by the procedures similar to those of Example18-b), except that air inlet temperature was 100° C. and dried for 1hour.c) The tablets were dried by the procedures similar to those of Example18-b), except that inlet air temperature was 100° C. and dried for 3hours.

Example 20

By the procedures similar to those of Example 18-a), there were obtainedtablets, each having 190 mg of weight, containing type C crystals ofanhydrous aripiprazole.

Example 21

By the procedures similar to those of Example 18-a), there were obtainedtablets, each having 190 mg of weight, containing type D crystals ofanhydrous aripiprazole.

Example 22

a) Aripiprazole hydrate crystals (156 g) obtained in Reference Example3, lactose (570 g), corn starch (100 g) and crystalline cellulose (100g) were charged in a fluidized bed granulating dryer (NEW-MARUMERIZER,NQ-160: manufactured by FUJI POWDAL CO., LTD.), and these granulatingingredients were mixed under fluidizing for about 3 minutes with aninlet air temperature at 60° C., air flow rate of 1.0 to 1.5 m³/min, androtating disc with rotary speed of 400 rpm. Further, the granulatingingredients were continued fluidizing under the same condition, andsprayed about 500 g of 4% aqueous solution of hydroxypropyl cellulose toobtain wet granules. The inlet air temperature was elevated up to 85°C., and dried until the temperature of the product was reached to 46° C.The obtained dried granules were sized by passing to a sieve of 850 μm.The dried granules contained 4.37% of water (measured by the methodaccording to Reference Example 4).

b) The dried granules (200 g) obtained in Example 22-a) were charged ina fluidized bed dryer (multiplex, MP-01: manufactured by POWREXCORPORATION), and dried at 85° C. of inlet air temperature, air flowrate of 0.5 m³/min for 2 hours. The dried granules contained 3.50% ofwater (measured by the method according to Reference Example 4).c) The dried granules (100 g) obtained in Example 22-a) were charged ina vacuum dryer (vacuum granulating dryer LCV-232: manufactured by TABAICO., LTD.), and dried 80° C. of tray temperature, about 760 mmHg ofdegree of vacuum for 2 hours. The dried granules were further driedsimilarly for 6 hours. The dried granules contained 3.17% of water (theproduct being dried for 2 hours: measured by the method according toReference Example 4). The further dried granules contained 2.88% ofwater (the product being dried for 6 hours: measured by the methodaccording to Reference Example 4).d) About 1% by weight of magnesium stearate was added to the sizedgranules being obtained in Example 22-b) and mixed, then the mixedgranules were supplied to a tablet machine (Single type Tablet machineNo. 2B: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and tablettedwith punch, there were obtained tablets, each having 191 mg of weight.e) About 1% by weight of magnesium stearate was added to the sizedgranules being obtained in Example 22-c) and mixed, then the mixedgranules were supplied to a tablet machine (Single type Tablet machineNo. 2B: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and tablettedwith punch, there were obtained tablets, each having 191 mg of weight.

Dissolution Test

Each tablets of the pharmaceutical solid oral preparations obtainedpreviously was kept, respectively under the open at 25° C./60% RH for 6months, and at 40° C./75% RH for 1 week, then their dissolution rateswere measured by the following methods. The dissolution rates obtainedfrom 60 minutes after the exposure are shown in Tables 2 and 3. Thedissolution rates after 60 minutes, using the tablets kept under theopen at 40° C./75% RH for 2 weeks, are shown in Tables 4 and 5. Thedissolution rates after 60 minutes, using the tablets kept under theopen condition at 40° C./75% RH for 1 week, are shown in Table 6.

Dissolution test equipment: USP

-   Model: NTR-6100 (manufactured by TOYAMA SANGYO CO., LTD.)-   Model: DT-610 (manufactured by JASCO CORPORATION)    a) Method of dissolution test of the 15 mg tablet

One tablet (containing 15 mg each of anhydrous aripiprazole or hydrate)was tested by using 900 ml of acetic acid buffer solution (pH 5.0)(Note: 1) as the test solution, and by rotating a paddle at 100 rpmaccording to the method of USP (United States Pharmacopoea) (Note: 2).

The test solutions obtained respectively from 10 minutes, 20 minutes, 30minutes, 45 minutes and 60 minutes after the start of test are named asT10, T20, T30, T45 and T60.

On the other hand, about 0.05 g of standard sample of aripiprazole wasweighed accurately, dissolved in ethanol (95%) so as to make exactly 50ml of ethanol solution. Twenty (20) ml of this ethanol solution wastaken accurately, and to prepared exactly 1000 ml of the standardsolution by adding 0.01 mol/liter of hydrochloric acid reagent solution(Note: 3).

The test solutions and the standard solution were subjected tofiltration, respectively by using a filter having micropores of 10 to 20μm in diameters, then each of the filtrates were introduced to aspectrophotometer installed with flow cell (cell length: 10 mm), and tomeasure the absorbance of wave length at 249 nm and absorbance of wavelength at 325 nm and determined the differences between absorbances tonamed as At10, At20, At30, At45, At60 and As, respectively.

After the measurements, the test solutions of T10, T20, T30 and T45 wereput back to the test vessels respectively. Further, similar procedureswere conducted to other 5 samples of the test solutions.

-   -   Dissolution rate (%) relating to the indicated amount of        aripiprazole m    -   Amount of the standard sample of aripiprazole (mg)×At ×As        ×9/5×20/C        wherein, At: At10, At20, At30, At45 or At60

As: standard solution

C: Indicated amount of aripiprazole (mg)

-   (Note: 1) Water was added to 1.97 g of acetic acid (100) and 9.15 g    of sodium acetate-trihydrate to make 1000 ml of solution (0.1    mol/l).-   (Note: 2) Paddle method-   (Note: 3) Water was added to 100 ml of 0.1 mol/l hydrochloric acid    (Note: 4) to make 1000 ml of solution.-   (Note: 4) Water was added to 0.9 ml of hydrochloric acid to make    1000 ml of solution.    b) Method of dissolution test of the 30 mg tablet

One tablet each of the pharmaceutical solid oral preparations(containing 30 mg each of anhydrous aripiprazole or hydrate) was testedby using 900 ml of acetic acid buffer solution (pH 4.5) (Note: 5) as thetest solution, and to conduct the test by rotating a paddle at 75 rpm inaccordance with the method of USP (United States Pharmacopoea) (Note:6).

The test solutions obtained respectively from 10 minutes, 20 minutes, 30minutes 45 minutes and 60 minutes after the start of test, were named asT10, T20, T30, T45 and T60.

On the other hand, about. 0.05 g of the standard sample of aripiprazolewas weighed accurately, and dissolved in ethanol (95%) so as to madeexactly 50 ml of the ethanol solution. Twenty (20) ml of the ethanolsolution was taken accurately, and prepared exactly 1000 ml of thestandard solution by adding 0.01 mol/liter of hydrochloric acid reagentsolution (Note: 7).

The test solutions and standard solution were subjected to filtration,respectively by using a filter having micropores of 10 to 20 μm indiameters, then each of the filtrates were introduced to aspectrophotometer in which a flow cell (cell length: 10 mm) wasinstalled, and measured the absorbance of wave length at 249 nm andabsorbance of wave length at 325 nm, and the difference between theseabsorbances were named as At10, At20, At30, At45, At60 and As,respectively.

After the measurements, the test solutions of T10, T20, T30 and T45 wereput back respectively to the test vessels. Further, similar procedureswere conducted to other 5 samples of the test solutions.

-   -   Dissolution rate (%) relating to the indicated amount of        aripiprazole=    -   Amount of the standard sample of aripiprazole (mg)×At ×As        ×9/5×20/C        wherein, At: At10, At20, At30, At45 or At60

As: standard solution

C: Indicated amount of aripiprazole (mg)

-   (Note: 5) Water was added to 1.91 g of acetic acid (100) and 2.99 g    of sodium acetate-trihydrate to made 1000 ml of solution (0.05    mol/1).-   (Note: 6) Paddle method-   (Note: 7) Water is added to 100 ml of 0.1 mol/1 hydrochloric acid    (Note: 8) to made 1000 ml of solution.-   (Note: 8) Water was added to 0.9 ml of hydrochloric acid to make    1000 ml of solution.

TABLE 2 Open at 25° C./60% RH Open at 40° C./75% RH After After Samplesused Initial 6 months Initial 1 week Tablet (15 mg) 83.4% 44.3% 83.4%44.1% of Referece Example 4 Tablet (15 mg) 90.1% 61.9% 90.1% 65.2% ofReference Example 5

TABLE 3 Open at 25° C./60% RH Open at 40° C./75% RH After After Samplesused Initial 6 months Initial 1 week Tablet (30 mg) 96.7% 77.1% 96.7%75.9% of Example 18-a) Tablet (30 mg) 96.5% 93.6% 95.0% 92.2% of Example17-b) Tablet (30 mg) 97.0% 96.3% 94.7% 94.8% of Example 17-c) Tablet (30mg) 97.2% 95.3% 97.2% 97.8% of Reference Example 18-b) Tablet (30 mg)97.8% 96.3% 97.8% 96.9% of Reference Example 18-c)

TABLE 4 Samples used Initial After 2 weeks Samples used Tablet 89.8%66.9% (30 mg) of Example 19-a) Tablet (30 mg) of — 79.8% Example 19-b)Tablet (30 mg) of — 85.9% Example 19-c)

TABLE 5 Samples used initial After 2 weeks Tablet (30 of 94.8% 94.7%Example 18-a) Tablet (30 mg) of 93.7% 93.1% Example 20 Tablet (30 mg) of94.8% 90.9% Example 21

TABLE 6 Samples used Initial After 1 weeks Tablet (30 mg of 96.5% 84.5%Example 22-d) Tablet (30 mg) of 92.5% 74.4% Example 22-e) (dreid for 2hours) Tablet (30 mg) of 96.2% 83.4% Example 22-e) (dreid for 6 hours)

-   (Note: Dissolution tests in Table 5 were conducted similarly to the    procedures in the above-mentioned “b) Method of dissolution test of    the 30 mg tablet” except that by using 900 ml of acetic acid buffer    solution (pH 4.0) as the test solution, and by rotating a paddle at    50 rpm.

As can be seen clearly from the data shown in Table 2, in comparisonwith the 15 mg tablet containing conventional anhydrous aripiprazolecrystals (Reference Example 4), the 15 mg tablet containing type Bcrystals of anhydrous aripiprazole (Reference Example 5) had thedissolution rate to maintain maximum drug concentration (Cmax), at pH5.0 after 60 minutes, even though such tablet was kept under the open at25° C./60% RH for 6 months and under the open at 40° C./75% RH for 1week.

As can be seen clearly from the data shown in Table 3, even though 30 mgtablets (Examples 17-b) and 17-c)) prepared from twice dried granules oftype B crystals of anhydrous aripiprazole, and 30 mg tablets (Examples18-b) and 18-c)) prepared from further dried pharmaceutical solid oralpreparation containing type B crystals of anhydrous aripiprazole weresubjected to keep under the open at 25° C./60% RH for 6 months or 40°C./75% RH for 1 week, the dissolution rates of these tablets obtained 60minutes after the test at pH 4.5 were not substantially lowered.

As can be seen clearly from the data shown in Table 4, when 30 mgtablets (Examples 19-a), 19-b) and 19-c)) containing conventionalanhydrous aripiprazole crystals were further dried and subjected to keepunder open at 40° C./75% RH for 2 weeks, then the dissolution rates ofthe tablets obtained 60 minutes after the test at pH 4.5 were thedissolution rates to maintain maximum drug concentration (Cmax).

As can be seen clearly from the data shown in Table 5, when 30 mg tablet(Example 18-a)) containing type B crystals of anhydrous aripiprazole, 30mg tablet (Example 20) containing type C crystals of anhydrousaripiprazole and 30 mg tablet (Example 21) containing type D crystals ofanhydrous aripiprazole were subjected to keep under open at 40° C./75%RH for 2 weeks, then the dissolution rates of the tablets obtained 60minutes after the test at pH 4.0 were not substantially lowered.

As can be seen clearly from the data shown in Table 6, when 30 mgtablets (Examples 22-d) and 22-e)) prepared from granules ofconventional aripiprazole hydrate being twice dried, and subjected tokeep under open at 40° C./75% RH for 1 week, then the dissolution ratesof the tablets obtained 60 minutes after the test at pH 4.5 were thedissolution rates to maintain maximum drug concentration (Cmax).

Sample Preparation 1 Anhydrous aripiprazole crystals B  5 mg Starch 131mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

Tablets containing the above ingredients in each tablet were prepared byformulation methods known to one skilled in the art of pharmaceuticalformulation.

Sample Preparation 2 Type C crystals of anhydrous aripiprazole  5 mgStarch 131 mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

In accordance with an ordinary method, tablet preparation, containingthe above-mentioned ingredients per 1 tablet was prepared.

Sample Preparation 3 Type D crystals of anhydrous aripiprazole  5 mgStarch 131 mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

In accordance with an ordinary method, tablet preparation, containingthe above-mentioned ingredients per 1 tablet was prepared.

Sample Preparation 4 Type E crystals of anhydrous aripiprazole  5 mgStarch 131 mg Magnesium stearate  4 mg Lactoce  60 mg Total 200 mg

In accordance with an ordinary method, tablet preparation, containingthe above-mentioned ingredients per 1 tablet was prepared.

Sample Preparation 5 Type F crystals of anhydrous aripiprazole  5 mgStarch 131 mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

In accordance with an ordinary method, tablet preparation, containingthe above-mentioned ingredients per 1 tablet was prepared.

Sample Preparation 6 Type G crystals of anhydrous aripiprazole  5 mgStarch 131 mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

In accordance with an ordinary method, tablet preparation, containingthe above-mentioned ingredients per 1 tablet was prepared.

Formulation Example

The following examples used aripiprazole drug substance made by firstmilling or pulverizing the conventional hydrate of aripiprazole and thenheating it to form the anhydrous form (anhydrous aripiprazole crystalsB).

Formulation Example 1

Flash-melt tablets were prepared as follows:

Intragranulation:

Mg. per Ingredient Percent w/w tablet Xylitol (300) Xylisorb 26 52Avicel ® PH 102 12 24 Calcium Silicate 43.35 86.7 Crospovidone 3 6Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaricacid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 8.5 Total weight 92.75185.5

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was then added and the mixtureblended for an additional three minutes. The blended formulation wascompacted at a pressure of 30-35 kgF/cm² in a commercial compactorequipped with an orifice such that the compacts therefrom are in theform of ribbons. The ribbons were passed through a 30 mesh (600 microns)screen to form stable granules of about 150 to 400 microns.

Mg. per Ingredient Percent w/w tablet Intragranulation 92.75 185.5Avicel ® PH 200 3 6 Crospovidone 4 8 Magnesium stearate 0.25 0.5 Totalweight 100 200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.3 kP (3.5 SCU) and disintegrated in10 seconds in 5 ml of water. The final, blend formulation demonstratedexcellent flow and was free of other problems such as chipping, cappingand sticking. It has been found that utilizing Avicel® PH 102 for theintragranulation and Avicel® PH 200 for the extragranulation ingredientenhanced the quality of the resultant tablets.

Formulation Example 2

Flash-melt tablets containing a combination of two grades of calciumsilicate were prepared as follows:

Intragranulation:

Mg. per Ingredient Percent w/w tablet Xylitol (300) Xylisorb 26 52Avicel ® PH 102 12 24 Calcium Silicate 33.35 66.7 (crystalline, alphatriclinic) Hubersorb 600 NF 10 20 (amorphous calcium silicate)Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5Total weight 92.75 185.5

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofFormulation Example 1.

Extragranulation Ingredients:

Mg. per Ingredient Percent w/w tablet Intragranulation 92.75 185.5Avicel ® PH 200 3 6 Crospovidone 4 8 Magnesium stearate 0.25 0.5 Totalweight 100 200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.0 kP (3.1 SCU) and disintegrated in10 seconds in 5 ml of water.

Formulation Example 3

Flash-melt tablets containing aripiprazole, an antischizophrenic drug,were prepared as follows:

Intragranulation

Mg. per Ingredient Percent w/w tablet Aripiprazole 15 30 Xylitol (300)Xylisorb 25 50 Avicel ® pH 102 6 12 Calcium Silicate 37 74 Crospovidone3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3Tartaric acid 2 4 Acesulfame K 2 4 Magneaium stearate 0.25 0.5 Totalweight 94.4 188.8

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofFormulation Example 1.

Extragranulation Ingredients:

Mg. per Ingredient Percent w/w tablet Intragranulation 94.4 188.8Avicel ® PH 200 1.1 2.2 Crospovidone 4 8 Magnesium stearate 0.5 1 Totalweight 100 200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.0 kP (3.1 SCU) and disintegrated in10 seconds in 5 ml of water.

Formulation Example 4

Flash-melt tablets containing aripiprazole were prepared as follows:

Intragranulation:

Mg. per Ingredient Percent w/w tablet Atipiprasole 0.5 1 Xylitol (300)Xylisorb 27 54 Avicel ® PH 102 12 24 Calcium Silicate 42 84 Crospovidone3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Totalweight 92.9 185.8

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofFormulation Example 1.

Extragranulation Ingredients:

Mg. per Ingredient Percent w/w tablet Intragranulation 92.9 185.8Avicel ® PH 200 2.6 5.2 Crospovidone 4 8 Magnesium stearate 0.5 1 Totalweight 100 200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.3 kP (3.5 SCU) and disintegrated in10 seconds in 5 ml of water.

1. Hydrate A of aripiprazole having a powder x-ray diffraction spectrumcomprising characteristic peaks at 2θ=12.6°, 15.4°, 17.3°, 18.0°, 18.6°,22.5°, and 24.8° using a Cu K_(α) x-ray.